8-Heteroaryl xanthine adenosine A2B receptor antagonists

ABSTRACT

The present invention relates generally to compounds of formula (I):  
                 
wherein X is a five or six-membered heteroaromatic ring, containing one to four heteroatoms, selected from nitrogen, oxygen, or sulfur, provided that at least one heteroatom is nitrogen; and 
         G 1  and G 2  are independently CH or N.        

     The present invention also relates to the preparation of the compounds, pharmaceutical formulations thereof, and their use in medicine as potent or selective A 2B  adenosine receptor antagonists and their uses for treating asthma, autoimmune diseases and retinal vascular diseases.

RELATED APPLICATION

This application is a division of U.S. application Ser. No. 10/357,865filed Feb. 3, 2003, which claims the benefit of U.S. ProvisionalApplication No. 60/353,317, filed Feb. 1, 2002, hereby incorporated byreference.

BACKGROUND OF THE INVENTION

The present invention relates to compounds having antagonistic activityon adenosine A_(2B) receptors. Such compounds are useful in medicamentsfor treating diseases responsive to reduced levels of A_(2B) receptorsas well as use as radioligands for studying biological activityassociated with the adenosine A_(2B) receptor.

Adenosine (Ado) is an autocoid (or local hormone) that modulatesnumerous functions in the cardiovascular and other organ systems. Theactions of Ado are mediated by at least four subtypes of cell surfacereceptors called A₁, A_(2A), A_(2B), and A₃. Because the ubiquity ofadenosine receptors (AdoRs) throughout the body of a human, theirindiscriminate activation may cause undesirable side effects. Therefore,new drug design approaches to achieve receptor and organ selectivity areneeded.

Recently significant advancement has been made in the understanding ofthe molecular pharmacology and physiology of A_(2B) adenosine receptors.However, due to the lack of highly potent and selective ligands for thisreceptor subtype, many questions about the patho-physiological role ofA_(2B) receptors have not yet been answered (Feoktistov and Biaggioni,1997; Feoktistov and Biaggioni, 1998). A_(2B) receptors have beenimplicated in the regulation of mast cell secretion (Feoktistov andBiaggioni 1995), gene expression (Boyle et al. 1996), cell growth (Dubeyet al., 1996), intestinal functions (Murthy et al., 1995),neurosecretion (Mateo et al., 1995), vascular tone (Haynes et al., 1995)and asthma (Feoktistov et al., 1998).

U.S. Pat. No. 6,117,878 to Linden discloses the use of 8-phenylsubstituted xanthines for the treatment of diseases induced byactivation of the adenosine A_(2B) receptor and mast cell activation.These disease states are disclosed as including asthma, myocardialreperfusion injury, allergic reactions including rhinitis, poison ivyinduced responses, urticaria, scleroderma arthritis, other autoimmunediseases and inflammatory bowel diseases. In general, antagonists of theA_(2B) adenosine receptor subtype are disclosed to haveanti-inflammatory action. U.S. Pat. No. 6,117,878 to Linden isincorporated by reference.

U.S. Patent Application 2002/0002142 to Belardinelli et al. disclosesthe use of A_(2B) adenosine receptor antagonist compounds for inhibitingmammalian cell proliferation in cells that express the A_(2B) adenosinereceptor including human retinal endothelial cells (HREC). Belardinellidiscloses such treatment for ischemic injury to retinal vessels, forexample, microvascular abnormalities of the retina, retinopathy,prematurity, macular degeneration, and diabetic retinopathy. U.S. PatentApplication 2002/0002142 to Belardinelli et al. is incorporated byreference.

The use of A_(2B) antagonists as antiasthmatic agents is supported bythe experimental observation that theophylline and enprofylline are usedas therapeutic agents (Feoktistov and Biaggioni 1997; Feoktistov et al.,1998). Theophylline is an alkyl-xanthine that is a weak nonselectiveadenosine antagonist (See Linden et al., Cardiovascular Biology ofPurines, eds. G. Burnstock, et al., 1998, pp. 1-20.) However, its use isassociated with unpleasant side effects, such as insomnia and diuresis.(See Vassallo et al., Mayo. Clin. Proc. 1998, 73, 346-354). In recentyears, the use of theophylline as a bronchodilator, for relief ofasthma, has been supplanted by drugs of other classes, i.e., selectiveβ₂-adrenergic agonists, corticosteroids, and recently leukotrieneantagonists. (See Drazen et al., New Eng. J. Med. 1999, 340, 197-206.).These compounds also have limitations, thus, the development of atheophylline-like drug with reduced side effects is still desirable.

It has been recognized that theophylline and its closely relatedanalogue caffeine block endogenous adenosine acting as a local modulatorof adenosine receptors in the brain and other organs at therapeuticallyuseful doses. (See Fredholm et al., Pharmacol. Rev. 1999, 51, 83-133.).In comparison to the other known actions of theophylline, e.g.,inhibition of phosphodiesterases, theophylline is more potent inantagonism of adenosine receptors.

As noted the xanthine derivative, enprofylline, is also used to treatasthma. Enprofylline has been reported to block A_(2B) adenosinereceptors. However, this compounds only weakly blocks A₁, A_(2A) and A₃adenosine receptors.

It has been reported that therapeutic concentrations of theophylline orenprofylline block human A_(2B) receptors, and it has been proposed thatantagonists selective for this subtype may have potential use asantiasthmatic agents. (See Feoktistov et al., Pharmacol. Rev. 1997, 49,381-402; and Robeva et al., Drug Dev. Res. 1996, 39, 243-252.Enprofylline has a reported K_(i) value of 7 μM and is somewhatselective in binding to human A_(2B) adenosine receptors. (See Robeva etal., Drug Dev. Res. 1996, 39, 243-252 and Linden et al., Vol. Pharmacol.1999, 56, 705-713.)

Adenosine A_(2B) receptors are expressed in some mast cells, such as theBR line of canine mastocytoma cells, which appear to be responsible fortriggering acute Ca²⁺ mobilization and degranulation. (See Auchampach etal., Mol. Pharmacol. 1997, 52, 846-S60 and Forsyth et al., Inflamm. Res.1999, 48, 301-307.) Adenosine A_(2B) receptors also trigger Ca²⁺mobilization, and participate in a delayed IL8 release from human HMC-1mast cells. Other functions associated with the A_(2B) AR are thecontrol of cell growth and gene expression, (See Neary et al., TrendsNeurosci. 1996, 19, 13-18.) endothelial-dependent vasodilation (SeeMartin et al., J Pharmacol. Exp. Ther. 1993, 265, 248-2,53.), and fluidsecretion from intestinal epithelia. (See Strohmeier, et al., J Biol.Chem. 1995, 270, 2387-2394.) Adenosine acting through A_(2B) receptorsubtype has also been reported to stimulate chloride permeability incells expressing the cystic fibrosis transport regulator. (See Clancy etal., Am. J Physiol. 1999, 276, C361-C369.)

Both of these xanthine derivatives, enprofylline and theophylline, areproven to be effective but with low potency and selectivity at theA_(2B) adenosine receptor subtype (theophylline A_(2B) binding affinityK_(i)=13 μM; enprofylline A_(2B) binding affinity K_(i)=7 μM).

Asthma is a complex disease involving the concerted actions of multipleinflammatory and immune cells, spasmogens, inflammatory mediators,cytokines and growth factors. Theophylline has significant side effectsthat may be related to its A₁ receptor antagonism. It is thereforebelieved that more potent and selective A_(2B) receptor antagonists willprovide enhanced asthma treatment.

The A₁, A_(2A) and A₃ adenosine receptors have been pharmacologicallycharacterized through the use of highly potent and selective agonistsand/or antagonists. In contrast the study of A_(2B) receptor has beenprecluded due to the lack of selective ligands. Researchers such asJacobson and his coworkers have proposed using the radioligand of7-amino-2-(2-4-furyl)-5-[2-(4-hydroxy-phenyl)ethyl]-amino[1,2,4]-triazolo-[1,5-a][1,3,5]-triazine([³H]-ZM241385) as useful radioligand for studying the A_(2B) adenosinereceptor subtype (Ji et al., 1999) even though [³H]-ZM241385 has a K_(D)value of 34 nM.

Jacobson and coworkers have also reported some xanthine derivativesendowed with good affinity to the adenosine receptors but withoutsignificant selectivity for the human A_(2B) adenosine receptor subtype(Kim et al., 1999; Jacobson et al., 1999). Some non-xanthine derivativesclosely related to ZM 241385 have also been synthesized, but, while someof the reported compounds displayed significant affinity to A_(2B)receptors, none of them possessed relevant selectivity versus the otherreceptor subtypes A₁, A_(2A) and A₃ (De Zwart et al., 1999).

Similarly, Jacobson and coworkers, with the aim of obtainingnon-xanthine antagonists for A_(2B) receptors, modified the structure of5-amino-9-chloro-2-(2-furanyl)[1,2,4]triazolo-[1,5-c]-quinazoline (CGS15943), a non selective adenosine receptor antagonist, which appeared tobe a suitable starting compound for adenosine receptor antagonists byappropriate substitutions at different positions. In particular animprovement of affinity to A_(2B) receptors was observed whenaminoacidic chains are appended to the amino group of position 5 (Kim etal., 1998).

U.S. Pat. No. 5,935,964 to Baraldi et al. discloses triazolo pyrimidineshave antagonist affinity for the A_(2A) receptor. Using these compoundsas a starting point, Baraldi et al. investigated a series ofpyrazolo[4,3-e]1,2,4-triazolo-[1,5-c]pyrimidine compounds for use asA_(2B) receptor antagonists. In particular the compounds with the freeamino group at the 5-position, and for example, a phenylethyl chain atthe N8 pyrazole nitrogen show good affinity to A_(2B) adenosinereceptors. However, none of these compounds demonstrated goodselectivity (Baraldi et al., 2001).

Linden, Jacobson and coworkers have also reported a series of anilidederivatives of 8-phenyl-xanthine carboxylic congeners that proved to bepotent and selective A_(2B) antagonists (Kim et al., 2000; Ji et al.,2001) and S-substituted 1,3,7-trialkyl xanthine derivatives (U.S. Pat.No. 5,861,405 to Jacobson et al.) While many of the Linden and Jacobsoncompounds have high adenosine A_(2B) potency, selectivity against otherhuman adenosine receptors are in most cases limited (PCT patentapplication WO 00/73307 by Linden, Jacobson et al., 2000).

We have now discovered additional novel xanthine compounds having highantagonist affinity for the A_(2B) receptor with varying levels ofaffinity and superior selectivity compared to compounds previouslyreported. The above noted references are incorporated herein byreference.

BRIEF SUMMARY OF THE INVENTION

Compounds useful as potent, yet selective modulators of adenosinereceptors, with activity as adenosine A_(2B) receptor antagonists, and,in some cases A₁ or A₃ antagonists, and methods of preparation and usethereof, are disclosed.

The compounds of the present invention have the following generalformula (I):

wherein

R¹ and R² are independently hydrogen, (C₁ to C₈)alkyl, (C₂ toC₈)alkenyl, (C₂ to C₈)alkynyl, (C₇ to C₁₄)aralkyl, (C₈ to C₁₄)aralkenyl,or (C₈ to C₁₄)aralkynyl;

R³ is hydrogen, (C₁ to C₄)alkyl, (C₂ to C₅)alkenyl, or (C₂ toC₅)alkynyl;

A is a carbon-carbon bond, alkyl chain of one to four carbons, alkenylchain of two to four carbons, or alkynyl chain of two to four carbons;

X is an optionally substituted five or six-membered heteroaromatic ring,containing one to four heteroatoms, selected from nitrogen, oxygen, orsulfur, provided that at least one heteroatom is nitrogen;

M is a (C₁ to C₈)alkylene, (C₂ to C₈)alkenylene, or (C₂ toC₈)alkynylene, wherein at least one of the carbon atoms of the alkylene,alkenylene, or alkynylene group is present as a carbonyl, and one ormore of the remaining carbon atoms of the alkylene, alkenylene, oralkynylene group may be replaced by —O—, —N(R⁷)—, —S—, —S(O)—, or—S(O)₂—;

G¹ and G² are independently CH or N;

R⁴, R⁵ and R⁶ are independently hydrogen, (C₁ to C₄)alkyl, (C₂ toC₅)alkenyl, (C₂ to C₅)alkynyl, optionally substituted (C₆ to C₁₀)aryl,(C₇ to C₁₄)aralkyl, (C₈ to C₁₄)aralkenyl, or (C₈ to C₁₄)aralkynyl, acyl,optionally substituted alkoxy, aralkoxyalkylthio, amino, substitutedamino, disubstituted amino, fluoro, chloro, bromo, iodo, nitro, cyano,azido, hydroxy, sulfhydryl, S(O)alkyl, S(O)₂alkyl, CO₂H, SO₃H; or

taken together with the carbon atoms to which they are attached eitherR⁴ and R⁵ or R⁵ and R⁶ form a five or six-membered heterocyclic orheteroaromatic ring containing one to four hetereoatoms selected fromnitrogen, oxygen, or sulfur; or

taken together with the carbon atoms to which they are attached eitherR⁴ and R⁵ or R⁵ and R⁶ may independently form a carbocyclic orheterocyclic fused ring selected from the group of fused ringscomprising —OCH₂O—, —OCH(R⁷)O—, —OC(R⁷)₂O—, —OCH₂CH₂O—, OCH₂CH₂—,—CH₂CH₂O—, —OCH₂CH₂CH₂—, —CH₂CH₂CH₂O—, —OCH═CH—, —CH═CH—O—, —OCH═CH—,—CH═CH—CH═CH, —CH₂CH₂CH₂— and —CH₂CH₂CH₂CH₂—;

R⁷ is hydrogen, (C₁ to C₄)alkyl, (C₂ to C₅) alkenyl, or (C₂ toC₅)alkynyl;

or a pharmaceutically acceptable salt thereof.

In another aspect this invention provides compounds of formula (I):

wherein

R¹ and R² are independently hydrogen, (C₁ to C₈)alkyl, (C₂ toC8)alkenyl, (C₂ to C₈)alkynyl, (C₇ to C₁₄)aralkyl, (C₈ to C₁₄)aralkenyl,or (C₈ to C₁₄)aralkynyl;

R³ is hydrogen, (C₁ to C₄)alkyl, (C₂ to C₅)alkenyl, or (C₂ toC₅)alkynyl;

A is a carbon-carbon bond, alkyl chain of one to four carbons, alkenylchain of two to four carbons, or alkynyl chain of two to four carbons;

X is a five or six-membered heteroaromatic ring, containing one to fourheteroatoms, selected from nitrogen, oxygen, or sulfur, provided that atleast one heteroatom is nitrogen, optionally substituted by one or twosubstituents selected from the group consisting of lower alkyl, amino,hydroxy, alkyloxy, acyloxy and acylamino;

M is a (C₁ to C₈)alkylene, (C₂ to C₈)alkenylene, or (C₂ toC₈)alkynylene, wherein at least one of the carbon atoms of the alkylene,alkenylene, or alkynylene group is present as a carbonyl, and one ormore of the remaining carbon atoms of the alkylene, alkenylene, oralkynylene group may be replaced by —O—, —N(R⁷)—, —S—, —S(O)—, —S(O)₂—;or a carbon substituted with a lower alkyl;

G¹ and G² are independently CH or N;

R⁴, R⁵ and R⁶ are independently hydrogen, (C₁ to C₄)alkyl, (C₂ toC₅)alkenyl, (C₂ to C₅)alkynyl, optionally substituted (C₆ to C₁₀)aryl,(C₇ to C₁₄)aralkyl, (C₈ to C₁₄)aralkenyl, or (C₈ to C₁₄)aralkynyl, acyl,optionally substituted alkoxy, aralkoxyalkylthio, amino, substitutedamino, disubstituted amino, fluoro, chloro, bromo, iodo, nitro, cyano,azido, hydroxy, sulfhydryl, S(O)alkyl, S(O)₂alkyl, CO₂H, SO₃H; or

taken together with the carbon atoms to which they are attached eitherR⁴ and R⁵ or R⁵ and R⁶ form a five or six-membered heterocyclic orheteroaromatic ring containing one to four hetereoatoms selected fromnitrogen, oxygen, or sulfur; or

taken together with the carbon atoms to which they are attached eitherR⁴ and R⁵ or R⁵ and R⁶ form a carbocyclic or heterocyclic fused ringselected from the group of fused rings comprising —OCH₂O—, —OCH(R⁷)O—,—OC(R⁷)₂O—, —OCH₂CH₂O—, OCH₂CH₂—, —CH₂CH₂O—, —OCH₂CH₂CH₂—, —CH₂CH₂CH₂O—,—OCH═CH—, —CH═CH—O—, —O—CH═CH—O—, —CH═CH—CH═CH—, —CH₂CH₂CH₂— and—CH₂CH₂CH₂CH₂—;

R⁷ is hydrogen, (C₁ to C₄)alkyl, (C₂ to C₅) alkenyl, or (C₂ toC₅)alkynyl; or a pharmaceutically acceptable salt thereof.

In a further aspect, this invention provides compounds of the followingformula (II):

wherein

R¹ and R² are independently hydrogen, (C₁ to C₈)alkyl, (C₂ toC₈)alkenyl, (C₂ to C₈)alkynyl, (C₇ to C₁₄)aralkyl, (C₈ to C₁₄)aralkenyl,or (C₈ to C₁₄)aralkynyl;

R³ is H or (C₁ to C₈)alkyl;

R⁹ is independently a phenyl or pyrazole ring; a phenyl or pyrazole ringsubstituted at any position with amino, lower alkyl, or carboxyl; or aphenyl or pyrazole ring substituted at any two positions with asubstituent selected from amino, lower alkyl, and carboxyl; or

R⁹ is selected from the group consisting of

or a pharmaceutically acceptable salts thereof.

In yet another aspect, the invention provides compounds of formula(III):

wherein

-   -   R¹ and R² are independently hydrogen, (C₁ to C₈)alkyl, (C₂ to        C₈)alkenyl, (C₂ to C₈)alkynyl, (C₇ to C₁₄)aralkyl, (C₈ to        C₁₄)aralkenyl, or (C₈ to C₁₄)aralkynyl;

R⁸ is phenyl, substituted phenyl, (C, to C₈)alkyl, or benzyl;

or a pharmaceutically acceptable salt thereof

The compounds can be used in a method for the treatment of diseasesmediated by adenosine A_(2B) receptors. Such diseases include, but arenot limited to chronic and acute inflammatory diseases involvingdegranulation of mast cells including asthma, chronic obstructivepulmonary disease, rheumatoid arthritis, allergic rhinitis, allergicdermatitis and bee sting; impaired sensitivity to insulin including Type2 diabetes or non-insulin dependent diabetes, pre-diabetic state, andimpaired glucose tolerance; diseases in which angiogenesis is a keycomponent of pathogenesis including solid tumors and angiogenicretinopathies; and apnea of preterm infants; myocardial reperfusioninjury, inflammatory bowel disease, and autoimmune diseases such asrheumatoid arthritis, multiple sclerosis (MS), and lupus erythematosis.

Similarly, the compounds can be used in a method for the treatment ofdiseases involving microvascular abnormalities of the retina that aremediated by adenosine A_(2B) receptors. Such diseases include, but arenot limited to, retinopathy, prematurity, macular degeneration, anddiabetic retinopathy.

The compounds can be used in a pharmaceutical formulation that includesa compound of the present invention and one or more excipients. Variouschemical intermediates can be used to prepare the compounds of thepresent invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1illustrates competition binding curves for compound AS29 to humancloned A₁, A_(2a), A_(2b), and A₃ adenosine receptors;

FIG. 2 illustrates competition binding curves for compound AS57 to humancloned A₁, A_(2a), A_(2b), and A₃adenosine receptors;

FIG. 3 illustrates competition binding curves for compound AS64 to humancloned A₁, A_(2a), A_(2b), and A₃ adenosine receptors;

FIG. 4 illustrates competition binding curves for compound AS68 to humancloned A₁, A_(2a), A_(2b), and A₃ adenosine receptors; and

FIG. 5 illustrates a Comparison between binding and functional data.

DETAILED DESCRIPTION OF THE INVENTION

The present application discloses compounds useful as potent, yetselective antagonists of adenosine receptors with particular utilitywith the adenosine A_(2B) receptor subtype, methods of preparation anduse thereof.

The compounds can be used in a pharmaceutical formulation that includesa compound of the present invention and one or more excipients. Variouschemical intermediates can be used to prepare the compounds of thepresent invention.

The compounds of the present invention have the following generalformula (I):

wherein

R¹ and R² are independently hydrogen, (C₁ to C₈)alkyl, (C₂ toC₈)alkenyl, (C₂ to C₈)alkynyl, (C₇ to C₁₄)aralkyl, (C₈ to C₁₄)aralkenyl,or (C₈ to C₁₄)aralkynyl;

R³ is hydrogen, (C₁ to C₄)alkyl, (C₂ to C₅)alkenyl, or (C₂ toC₅)alkynyl;

A is a carbon-carbon bond, alkyl chain of one to four carbons, alkenylchain of two to four carbons, or alkynyl chain of two to four carbons;

X is an optionally substituted five or six-membered heteroaromatic ring,containing one to four heteroatoms, selected from nitrogen, oxygen, orsulfur, provided that at least one heteroatom is nitrogen;

M is a (C₁ to C₈)alkylene, (C₂ to C8)alkenylene, or (C₂ toC₈)alkynylene, wherein at least one of the carbon atoms of the alkylene,alkenylene, or alkynylene group is present as a carbonyl, and one ormore of the remaining carbon atoms of the alkylene, alkenylene, oralkynylene group may be replaced by —O—, —N(R⁷)—, —S—, —S(O)—, or—S(O)₂—;

G¹ and G² are independently CH or N;

R⁴, R⁵ and R⁶ are independently hydrogen, (C₁ to C₄)alkyl, (C₂ toC₅)alkenyl, (C₂ to C₅)alkynyl, optionally substituted (C₆ to C₁₀)aryl,(C₇ to C₁₄)aralkyl, (C₈ to C₁₄)aralkenyl, or (C₈ to C₁₄)aralkynyl, acyl,optionally substituted alkoxy, aralkoxyalkylthio, amino, substitutedamino, disubstituted amino, fluoro, chloro, bromo, iodo, nitro, cyano,azido, hydroxy, sulfhydryl, S(O)alkyl, S(O)₂alkyl, CO₂H, SO₃H; or

taken together with the carbon atoms to which they are attached eitherR⁴ and R⁵ or R⁵ and R⁶ form a five or six-membered heterocyclic orheteroaromatic ring containing one to four hetereoatoms selected fromnitrogen, oxygen, or sulfur; or

taken together with the carbon atoms to which they are attached eitherR⁴ and R⁵ or R⁵ and R⁶ may independently form a carbocyclic orheterocyclic fused ring selected from the group of fused ringscomprising —OCH₂O—, —OCH(R⁷)O—, —OC(R⁷)₂O—, —OCH₂CH₂O—, OCH₂CH₂—,—CH₂CH₂O—, —OCH₂CH₂CH₂—, —CH₂CH₂CH₂O—, —OCH═CH—, —CH═CH—O—, —O—CH═CH—O—,—CH═CH—CH═CH—, —CH₂CH₂CH₂— and —CH₂CH₂CH₂CH₂—;

R⁷ is hydrogen, (C₁ to C₄)alkyl, (C₂ to C₅) alkenyl, or (C₂ toC₅)alkynyl; or a pharmaceutically acceptable salt thereof.

In another aspect this invention provides compounds of formula (I):

wherein

R¹ and R² are independently hydrogen, (C₁ to C₈)alkyl, (C₂ toC₈)alkenyl, (C₂ to C₈)alkynyl, (C₇ to C₁₄)aralkyl, (C₈ to C₁₄)aralkenyl,or (C₈ to C₁₄)aralkynyl;

R³ is hydrogen, (C₁ to C₄)alkyl, (C₂ to C₅)alkenyl, or (C₂ toC₅)alkynyl;

A is a carbon-carbon bond, alkyl chain of one to four carbons, alkenylchain of two to four carbons, or alkynyl chain of two to four carbons;

X is a five or six-membered heteroaromatic ring, containing one to fourheteroatoms, selected from nitrogen, oxygen, or sulfur, provided that atleast one heteroatom is nitrogen, optionally substituted by one or twosubstituents selected from the group consisting of lower alkyl, amino,hydroxy, alkyloxy, acyloxy and acylamino;

M is a (C₁ to C₈)alkylene, (C₂ to C₈)alkenylene, or (C₂ toC₈)alkynylene, wherein at least one of the carbon atoms of the alkylene,alkenylene, or alkynylene group is present as a carbonyl, and one ormore of the remaining carbon atoms of the alkylene, alkenylene, oralkynylene group may be replaced by —O—, —N(R⁷)—, —S—, —S(O)—, —S(O)₂—;or a carbon substituted with a lower alkyl;

G¹ and G² are independently CH or N;

R⁴, R⁵ and R⁶ are independently hydrogen, (C₁ to C₄)alkyl, (C₂ toC₅)alkenyl, (C₂ to C₅)alkynyl, optionally substituted (C₆ to C₁₀)aryl,(C₇ to C₁₄)aralkyl, (C₈ to C₁₄)aralkenyl, or (C₈ to C₁₄)aralkynyl, acyl,optionally substituted alkoxy, aralkoxyalkylthio, amino, substitutedamino, disubstituted amino, fluoro, chloro, bromo, iodo, nitro, cyano,azido, hydroxy, sulfhydryl, S(O)alkyl, S(O)₂alkyl, CO₂H, SO₃H; or

taken together with the carbon atoms to which they are attached eitherR⁴ and R⁵ or R⁵ and R⁶ form a five or six-membered heterocyclic orheteroaromatic ring containing one to four hetereoatoms selected fromnitrogen, oxygen, or sulfur; or

taken together with the carbon atoms to which they are attached eitherR⁴ and R⁵ or R⁵ and R⁶ form a carbocyclic or heterocyclic fused ringselected from the group of fused rings comprising —OCH₂O—, —OCH(R⁷)O—,—OC(R⁷)₂O—, —OCH₂CH₂O—, OCH₂CH₂—, —CH₂CH₂O—, —OCH₂CH₂CH₂—, —CH₂CH₂CH₂O—,—OCH═CH—, —CH═CH—O—, —O—CH═CH—O—, —CH═CH—CH═CH—, —CH₂CH₂CH₂— and—CH₂CH₂CH₂CH₂—;

R⁷ is hydrogen, (C₁ to C₄)alkyl, (C₂ to C₅) alkenyl, or (C₂ toC₅)alkynyl; or a pharmaceutically acceptable salt thereof.

In a further aspect, this invention provides compounds of the followingformula (II):

wherein

R¹ and R² are independently hydrogen, (C₁ to C₈)alkyl, (C₂ toC₈)alkenyl, (C₂ to C₈)alkynyl, (C₇ to C₁₄)aralkyl, (C₈ to C₁₄)aralkenyl,or (C₈ to C₁₄)aralkynyl;

R³ is H or (C₁ to C₈)alkyl;

R⁹ is independently a phenyl or pyrazole ring; a phenyl or pyrazole ringsubstituted at any position with amino, lower alkyl, or carboxyl; or aphenyl or pyrazole ring substituted at any two positions with asubstituent selected from amino, lower alkyl, and carboxyl; or

R⁹ is selected from the group consisting of

or a pharmaceutically acceptable salts thereof.

In yet another aspect, the invention provides compounds of formula(III):

wherein

R¹ and R² are independently hydrogen, (C₁ to C₈)alkyl, (C₂ toC₈)alkenyl, (C₂ to C₈)alkynyl, (C₇ to C₁₄)aralkyl, (C₈ to C₁₄)aralkenyl,or (C₈ to C₁₄)aralkynyl;

R⁸ is phenyl, substituted phenyl, (C₁ to C₈)alkyl, or benzyl;

or a pharmaceutically acceptable salt thereof

As used herein the term “very potent adenosine A_(2B) receptorantagonist” means a compound able to prevent the inhibition of anadenosine A_(2B) receptor agonist and having a binding to humanadenosine A_(2B) receptor (K_(i)) of less than 2000 nM, preferably lessthan 150 nM, and most preferably less than 50 nM. The term “highlypotent adenosine A_(2B) receptor antagonist” means a very potentadenosine A_(2B) receptor antagonist having a binding affinity to humanadenosine A_(2B) receptor (K_(i)) of less than 150 nM.

As used herein the term “highly selective adenosine A_(2B) receptorantagonist” means a very potent adenosine A_(2B) receptor antagonisthaving a binding affinity to human adenosine receptor subtypes A₁,A_(2A) and A₃ (K_(i)) of greater than 1,000 nM.

As used herein the term “lower alkyl” means a monovalent radical,straight or branched chain, derived from the corresponding alkane havingone to ten carbon atoms, i.e., methyl, ethyl, propyl, isopropyl,n-butyl, sec-butyl, t-butyl, pentyl (all isomers), etc. Likewise, “loweralkylene” means a divalent radical of the corresponding alkane. Further,as used herein, other moieties having names derived from alkanes, suchas alkoxyl, alkanoyl, alkenyl, cycloalkenyl, etc. when modified by“lower,” have carbon chains of ten or less carbon atoms. In those caseswhere the minimum number of carbons are greater than one, e.g., alkenyl(minimum of two carbons) and cycloalkyl, (minimum of three carbons), itis to be understood that “lower” means at least the minimum number ofcarbons.

As used herein the term “amino acid” means an alpha amino acid selectedfrom those amino acids that naturally occur in proteins but withoutregard for specific stereochemical properties. The term “protected aminoacid” means an amino acid of which the alpha amino group has beenconverted to a less reactive moiety, but a moiety that can be convertedback to the amino group with relative ease. The terms “amino acidresidue” and “amino acid moiety” are use synonymously herein.

As used herein, the term “substituted alkyl” refers to an alkyl group,preferably of from 1 to 10 carbon atoms (“substituted lower alkyl”),having from 1 to 5 substituents, and preferably 1 to 3 substituents,selected from the group consisting of alkoxy, substituted alkoxy,cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino,aminoacyl, aminoacyloxy, oxyacylamino, cyano, halogen, hydroxyl, keto,thioketo, carboxyl, carboxylalkyl, thiol, thioalkoxy, substitutedthioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic,hydroxyamino, alkoxyamino, nitro, —S(O)-alkyl, —S(O)-substituted alkyl,—S(O)-aryl, -S(O)-heteroaryl, —S(O)₂-alkyl, —S(O)₂-substituted alkyl,—S(O)₂-aryl, —S(O)₂-heteroaryl, and mono- and di-alkylamino, mono- anddi-(substituted alkyl)amino, mono- and di-arylamino, mono- anddi-heteroarylamino, mono- and di-heterocyclic amino, and asymmetricdi-substituted amines having different substituents selected from thegroup consisting of alkyl, aryl, heteroaryl and heterocyclic. As usedherein, other moieties having, the prefix “substituted” are intended toinclude one or more of the substituents listed above.

As used herein, the term “alkoxy” refers to the group “alkyl-O—”, wherealkyl is as defined above. Preferred alkoxy groups include, by way ofexample, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy,sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.

As used herein, the term “alkenyl” refers to alkenyl groups preferablyhaving from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atomsand having at least 1 and preferably from 1-2 sites of alkenylunsaturation. Preferred alkenyl groups include ethenyl (—CH═CH₂),n-propenyl (—CH₂CH═CH₂), iso-propenyl (—C(CH₃)═CH₂), and the like.

As used herein, the term “alkynyl” refers to alkynyl groups preferablyhaving from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atomsand having at least 1 and preferably from 1-2 sites of alkynylunsaturation.

As used herein, the term “acyl” refers to the groups alkyl-C(O)—,substituted alkyl C(O)—, cycloalkyl-C(O)—, substituted cycloalkyl-C(O)—,aryl-C(O)—, substituted aryl-C(O)—, heteroaryl-C(O)— andheterocyclic-C(O)— where alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, aryl, heteroaryl and heterocyclic are as definedherein.

As used herein, the term “acylamino” refers to the group —C(O)NRR whereeach R is independently hydrogen, alkyl, substituted alkyl, aryl,substituted aryl, heteroaryl, or heterocyclic, wherein alkyl,substituted alkyl, aryl, heteroaryl and heterocyclic are as definedherein.

As used herein, the term “aryl” refers to an unsaturated aromaticcarbocyclic group of from 6 to 14 carbon atoms having a single ring,(e.g., phenyl) or multiple condensed (fused) rings (e.g., naphthyl oranthryl). Preferred aryls include phenyl, naphthyl and the like. Unlessotherwise constrained by the definition for the aryl substituent, sucharyl groups can optionally be substituted with from I to 5 substituentsand preferably 1 to 3 substituents selected from the group consisting ofacyloxy, hydroxy, acyl, alkyl, alkoxy, alkenyl, alkynyl, substitutedalkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl,amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy,azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl,heteroaryloxy, heterocyclic, heterocyclooxy, aminoacyloxy, oxyacylamino,thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy,—S(O)-alkyl, —S(O)-substituted alkyl, —S(O)-aryl, —S(O)-heteroaryl,—S(O)₂-alkyl, —S(O)₂-substituted alkyl, —S(O)₂-aryl, —S(O)₂-heteroaryl,trihalomethyl. Preferred substituents include alkyl, alkoxy, halo,cyano, nitro, trihalomethyl, and thioalkoxy.

As used herein, the term “cycloalkyl” refers to cyclic alkyl groups offrom 3 to 12 carbon atoms having a single cyclic ring or multiplecondensed rings. Such cycloalkyl groups include, by way of example,single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl,cyclooctyl, and the like, or multiple ring structures such as adamantyl,and the like.

As used herein, the terms “halo” or “halogen” refers to fluoro, chloro,bromo and iodo and preferably is fluoro, bromo or chloro.

As used herein, the term “heteroaryl” refers to an aromatic carbocyclicgroup of from 1 to 15 carbon atoms and 1 to 4 heteroatoms selected fromthe group consisting of oxygen, nitrogen and sulfur within at least onering (if there is more than one ring).

Unless otherwise constrained by the definition for the heteroarylsubstituent, such heteroaryl groups can be optionally substituted withfrom 1 to 5 substituents and preferably 1 to 3 substituents selectedfrom the group consisting of acyloxy, hydroxy, acyl, alkyl, alkoxy,alkenyl, alkynyl, substituted alkyl, substituted alkoxy, substitutedalkenyl, substituted alkynyl, amino, substituted amino, aminoacyl,acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl,cyano, halo, nitro, heteroaryl, heteroaryloxy, heterocyclic,heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substitutedthioalkoxy, thioaryloxy, thioheteroaryloxy, —S(O)-alkyl,—S(O)-substituted alkyl, —S(O)-aryl, —S(O)-heteroaryl, —S(O)₂-alkyl,—S(O)₂-substituted alkyl, —S(O)₂-aryl, —S(O)₂-heteroaryl, trihalomethyl.Preferred substituents include alkyl, alkoxy, halo, cyano, nitro,trihalomethyl, and thioalkoxy. Such heteroaryl groups can have a singlering (e.g., pyridyl or furyl) or multiple condensed rings (e.g.,indolizinyl or benzothienyl).

“Heterocycle” or “heterocyclic” refers to a monovalent saturated orunsaturated carbocyclic group having a single ring or multiple condensedrings, from 1 to 15 carbon atoms and from 1 to 4 hetero atoms selectedfrom the group consisting of nitrogen, sulfur or oxygen within the ring.Such heterocyclic groups are optionally substituted with 1 to 5substituents selected from the group consisting of alkyl, substitutedalkyl, alkoxy, substituted alkoxy, aryl, aryloxy, halo, nitro,heteroaryl, thiol, thioalkoxy, substituted thioalkoxy, thioaryloxy,trihalomethyl, and the like. Such heterocyclic groups can have a singlering or multiple condensed rings.

As to any of the above groups that contain 1 or more substituents, it isunderstood, that such groups do not contain any substitution orsubstitution patterns which are sterically impractical and/orsynthetically non-feasible.

“Pharmaceutically acceptable salts” refers to pharmaceuticallyacceptable salts of a compound of the general formula of the presentinvention, which salts are derived from a variety of organic andinorganic counter ions well known in the art and include, by way ofexample only, sodium, potassium, calcium, magnesium, ammonium,tetraalkylammonium, and the like; and when the molecule contains a basicfunctionality, salts of organic or inorganic acids, such ashydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate,oxalate and the like can be used as the pharmaceutically acceptablesalt.

The term “protecting group” or “blocking group” refers to any groupwhich when bound to one or more hydroxyl, amino or carboxyl groups ofthe compounds (including intermediates thereof such as the aminolactams,aminolactones, etc.) prevents reactions from occurring at these groupsand which protecting group can be removed by conventional chemical orenzymatic steps to reestablish the hydroxyl, amino or carboxyl group.Preferred removable amino blocking groups include conventionalsubstituents such as t-butyoxycarbonyl (t-BOC), benzyloxycarbonyl (CBZ),and the like which can be removed by conventional conditions compatiblewith the nature of the product.

Those skilled in the art of organic chemistry will appreciate thatreactive and fragile functional groups often must be protected prior toa particular reaction, or sequence of reactions, and then restored totheir original forms after the last reaction is completed. Usuallygroups are protected by converting them to a relatively stablederivative. For example, a hydroxyl group may be converted to an ethergroup and an amino converted to an amide or carbamate. Methods ofprotecting and de-protect, also know as “blocking” and “de-blocking,”are well know and widely practiced in the art, e.g., see T. Green,Protective Groups in Organic Synthesis, John Wiley, New York (1981) orProtective Groups in Organic Chemistry, Ed. J. F. W. McOmie, PlenumPress, London (1973).

Representative example compounds include: Example Compound NumberCompound Name AS38-(3-amino-1-methyl-1H-pyrazol-5-yl)-1,3-dipropyl-3,7-dihydro-1H-purine-2,6-dione AS4[3-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetra-hydro-1H-purin-8-yl)isoxazol-5-yl]methyl-benzoate AS78-(1-methyl-4-nitro-1H-pyrrol-2-yl)-1,3-dipropyl-3,7-dihydro-1H-purine-2,6-dione AS84-{[5-(1,3-dipropyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-pur-in-8-yl)-1-methyl-1H-pyrazol-3-yl]amino}-4-oxobutanoic acid AS9 tert-butyl4-{[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]amino}-4-oxobutylcarbamate AS104-{[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]amino}-4-oxobutan-1-aminium AS11N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-phenylacetamide AS122-(2,4-dichlorophenoxy)-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide AS132-(3-methoxyphenyl)-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide AS14N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(4-isobutylphenyl)acetamide AS15N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(4-nitrophenyl)acetamide AS162-[4-benzyloxyphenyl]-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide AS172-[4-hydroxyphenyl]-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide AS18(2S)-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-phenylpropanamide AS19(2R)-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-phenylpropanamide AS20{3-[(E)-2-(1,3-dipropyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)vinyl]isoxazol-5-yl}methyl benzoate AS212-(4-chlorophenoxy)-N-[5-(1,3-dipropyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide AS22N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(4-fluorophenyl)acetamide AS232-(4-methoxyphenyl)-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide AS24N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(3-chlorophenyl)acetamide AS25N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(3-fluorophenyl)acetamide AS26N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-[4-(N,N-dimethylamino)phenyl]acetamide AS27N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(4-chlorophenyl)acetamide AS282-(3,4-dimethoxyphenyl)-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide AS29N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(4-{[2-(trifluoromethyl)benzyl]oxy}phenyl)acetamideAS30N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(4-{[3-(trifluoromethyl)benzyl]- oxy}phenyl)acetamideAS31N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(4-{4-nitro-benzyloxy}phenyl)acetamide AS32N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-[4-(trifluoromethyl)phenyl]acetamide AS33 Phenyl4-[(E)-2-(7-methyl-1,3-dipropyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)vinyl]-1-methyl-1H-pyrrole-2-carboxylate AS35N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-5-yl]-2-phenylacetamide AS368-(1-methyl-3-nitro-1H-pyrazol-5-yl)-1,3-dipropyl-3,7-dihydro-1H-purine-2-,6-dione AS378-(5-amino-1-methyl-1H-pyrazol-3-yl)-1,3-dipropyl-3,7--dihydro-1H-purine-2,6-dione AS388-(3-amino-1-methyl-1H-pyrazol-5-yl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione AS40N-[5-(2,6-dioxo-1,3-dimethyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-phenylacetamide AS43N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(3,4-difluorophenyl)acetamide AS442-(2,3,4-trimethoxyphenyl)-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide AS53N-[4-(dimethylamino)phenyl]-N′-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]urea AS54N-(3-chlorophenyl)-N′-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]urea AS55N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-N′-(3-methoxyphenyl)urea AS562-[4-(benzyloxy)-3-methoxyphenyl]-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamideAS57 2-(1,3-benzodioxol-5-yl)-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide AS58N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(4-hydroxy-3-methoxyphenyl)acetamide AS59N-(4-methylphenyl)-2-{[5-(1,3-dipropyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]oxy}acetamide AS60N-(4-bromophenyl)-2-{[3-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-5-yl]oxy}acetamide AS61N-(4-fluorophenyl)-2-{[3-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-5-yl]oxy}acetamide AS622-{[3-(1,3-diisobutyl-2,6-dioxo-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-5-yl]oxy}-N-(4-fluorophenyl)acetamide AS632-{[3-(1,3-diisobutyl-2,6-dioxo-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methy-1-1H-pyrazol-5-yl]oxy}-N-(4-bromophenyl)acetamide AS642-{[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]oxy}-N-(4-fluorophenyl)acetamide AS652-{[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]oxy}-N-(4-bromophenyl)acetamide AS662-{[5-(1,3-diisobutyl-2,6-dioxo-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methy-1-1H-pyrazol-3-yl]oxy}-N-(4-fluorophenyl)acetamide AS672-{[5-(1,3-diisobutyl-2,6-dioxo-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methy-1-1H-pyrazol-3-yl]oxy}-N-(4-bromophenyl)acetamide AS68N-1,3-benzodioxol-5-yl-2-{[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]oxy}acetamide AS692-{[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]oxy}-N-(4-methoxyphenyl)acetamide AS11,3-di-n-propyl-8-(1-methyl-5-carboxy-1-H-pyrazol-3-yl)-xanthine AS491-[5-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-3-(4-methoxy-phenyl)-urea AS911,3-di-n-propyl-8-{5-[(4-sec-butyl-phenylcarbamoyl)-methoxy]-2-methyl-2H-pyrazole-3-yl}-xanthine AS921,3-di-n-propyl-8-{5-[(4-methyl-phenylcarbamoyl-methoxy]-2-methyl-2H-pyrazole-3-yl}-xanthine AS931,3-di-n-propyl-8-{5-[(4-(morpholine-4-yl)-phenylcarbamoyl)-methoxy]-2-methyl-2H-pyrazole-3-yl}-xanthine AS951,3-di-n-propyl-8-{5-[(4-carboxy-phenylcarbamoyl)-methoxy]-2-methyl-2H-py-razole-3-yl}-xanthine AS991,3-di-n-propyl-8-{5-[(3,4-dime-thyl-phenylcarbamoyl)-methoxy]-2-methyl-2H-pyrazole-3-yl}-xanthine AS1001,3-di-n-propyl-8-{5-[(3,4-dimethyl-phenylcar-bamoyl)-methoxy]-2-methyl-2H-pyrazole-3-yl}-xanthine AS1011,3-di-n-propyl-8-{5-[(3,4-dimethoxy-phenylcarbamoyl)-methoxy]-2-methyl-2H-pyrazole-3-yl}-xanthine AS891,3-di-n-propyl-8-{5-[(pyri-din-4yl)-methoxy]-2-methyl-2H-pyrazole-3-yl}-xanthine AS701,3-di-n-propyl-8-{5-[2-oxo-2-(4-phenyl-piperazin-1-yl)-ethoxy]-2-methyl-2H-pyrazole-3-yl}-xanthine AS728-(5-{2-[4-(4-Fluoro-pheny-1)-piperazin-1-yl]-2-oxo-ethoxy}-2-methyl-2H-pyrazol-3-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione AS871,3-di-n-propyl-8-{5-[2-Oxo-2-(4-methyl-piperazin-1-yl)-ethoxy]-2-methyl-2H-pyrazole-3-yl}-xanthine AS908-(5-{2-[4-(4-Benzyl-pheny-1)-piperazin-1-yl]-2-oxo-ethoxy}-2-methyl-2H-pyrazol-3-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione AS961,3-di-allyl-8-{5-[2-oxo-2-(4-phenyl-piperazin-1-yl)-ethoxy]-2-methyl-2H-pyrazole-3-yl}-xanthine AS741,3-di-n-propyl-8-{3-[(3,4-me-thylendioxy-phenylcarbamoyl)-methoxy]-isoxazol-5-yl}-xanthine AS761,3-di-n-propyl-8-{3-[(3,4-dimethoxy-phenylcarbamoyl)-methoxy]-isoxazol-5-yl}-xanthine AS731,3-di-n-propyl-8-{3-[(4-fluoro--phenylcarbamoyl)-methoxy]-isoxazol-5-yl}-xanthine AS751,3-di-n-propyl-8-{3-[(4-methoxy-phenylcarbamoyl)-methoxy]-isoxazol-5-yl}-xanthine AS811,3-di-n-propyl-8-{6-[(4-iodo-phenylcarbamoyl)-metho-xy]-pyridin-3-yl}-xanthine AS851,3-di-n-propyl-8-{6-[(4-iodo-pheny-lcarbamoyl)-methoxy]-pyridazin-3-yl}-xanthine AS68aN-1,3-benzodioxol-5-yl-2-{[5-(2,6-dioxo-1,3-diallyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]oxy}acetamide AS941,3-di-n-propyl-8-{5-[(4-(ethoxycarbonyl)-phenylcarbamoyl)-methoxy]-2-met-hyl-2H-pyrazole-3-yl}-xanthine AS1031,3-di-n-propyl-8-(2-hydroxypyridin-5-yl)-xanthine AS1051,3-diallyl-8-{5-[2-oxo-2-(4-(pyridin-2-yl)-piperazin-1-yl)-ethoxy]-2-met-hyl-2H-pyrazole-3-yl}-xanthine AS1061,3-diallyl-8-{5-[2-oxo-2-(4-(pyrimidin-2-yl)-piperazin-1-yl)-ethoxy]-2-m-ethyl-2H-pyrazole-3-yl}-xanthine AS1091,3-di-n-propyl-8-{5-[(4-(aminosulfonyl)phenylcarbamoyl)-methoxy]-2-methy-1-2H-pyrazole-3-yl}-xanthineSynthesis of Compounds

The compounds of the present invention may be synthesized by anysuitable means. However, the 8-heteroaryl-xanthine derivatives of thepresent invention are preferably synthesized by condensation of asuitably substituted heteroaryl-carboxylic acid with a1,3-disubstituted-5,6-diaminouracil to form an amide, which issubsequently cyclized to give a 1,3-disubstituted-8-heteroaryl-xanthine.

If desired, reaction of this product under conditions commonly employedby one skilled in the art would provide additional compounds of thepresent invention. For example, 1,3-disubstituted-8-heteroaryl-xanthinescontaining a primary amine on the heteroaryl moiety could be furtherreacted with an appropriate carboxylic acid, acid halide, carboxylicacid ester, or isocyanate under conditions widely known to those skilledin the art to provide the corresponding amides or ureas of the presentinvention.

Similarly, the 1,3-disubstituted-8-heteroaryl-xanthines containing ahydroxyl group attached to the heteroaryl moiety might be reacted with asuitable acyl ester, acid halide, α-halocarbonyl compound, isocyanate,sulfinyl halide or sulfonyl halide to afford the respective ester,β-oxycarbonyl compound, carbamate, sulfinate, or sulfonate. A furtherexample can be seen in which a 1,3-disubstituted-8-heteroaryl-xanthinecontaining a carboxylic acid attached to the heteroaryl moiety may bereacted with an appropriate aniline, heteroarylamine, alkylamine, oraralkylamine to afford the corresponding amide.

It will be recognized by one skilled in the art that numerous otherpossibilities are conceivable in the substituent attached to theheteroaryl moiety and the functional group it is reacted with. It willalso be recognized that the suggested additional reactions are notexhaustive, but merely illustrative.

In general, the compounds of the present invention are prepared asdepicted in the accompanying schemes. As shown in Scheme 1, a1,3-disubstituted-5,6-diaminouracil (Compound 2) may be dissolved in anappropriate volume of a lower alcohol with an appropriate heteroarylcarboxylic acid (Compound 3) and a suitable coupling agent, such as3-ethyl-1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(EDCI) or 1,3-dicyclohexylcarbodiimide (DCC), at a temperature of 5 to70° C., for a period of 1 to 24 hours.

After removing the residual solvent, the intermediate amide is treatedwith an excess of an aqueous basic solution, such as sodium hydroxide orpotassium hydroxide at a temperature of 30 to 100° C. for 1 to 12 hoursto afford the desired 8-(aminoheteroaryl)-1,3-disubstituted-xanthine(Compound 4).

After cooling the resulting clear aqueous solution to room temperature,the solution is typically acidified to approximately pH=5 using asuitable inorganic acid, such as concentrated HCl, until theintermediate 8-(aminoheteroaryl)-1,3-disubstituted-xanthineprecipitates. The precipitated intermediate may then be collected byfiltration or centrifugation further purifying, if desired, byrecrystallization from an appropriate solvent or combination of solventsor by chromatography.

A solution of the requisite carboxylic acid (Compound 5) may then beconverted to the corresponding acyl halide by suspending in theappropriate halogenating reagent, such as thionyl chloride, phosphorusoxychloride, thionyl bromide, phosphorus trichloride, or phosphorustribromide, optionally in the presence of a suitable solvent, such asmethylene chloride, chlorform, 1,2-dichloroethane, 1,4-dioxane, ordiethyl ether, and warming to between 30 and 90° C. for 1 to 18 hours.

After removal of the excess halogenating reagent, a solution of theintermediate 8-(aminoheteroaryl)-1,3-disubstituted-xanthine and asuitable base, such as triethylamine, diethylisopropylamine, ordiisopropylethylamine, is added to the acyl halide dissolved in anappropriate solvent. After stirring the mixture at 10 to 80° C. for 1 to36 hours, the mixture is evaporated, and the residue partitioned betweenan organic solvent and a saturated aqueous solution of sodiumbicarbonate. After drying the organic extract, the desired product istypically purified by column chromatography on silica gel.

Alternatively, compounds of the present invention may be prepared asdepicted in Scheme 2. In this sequence,1,3-disubstituted-5,6-diaminouracils (Compound 2) may be condensed withheteroarylcarboxylic acids possessing an ethoxycarbonylmethoxy groupattached to the heteroaryl moiety. Such condensation may be effected bytreating a solution of the 1,3-disubstituted-5,6-diaminouracil (Compound2) in an appropriate volume of a lower alcohol with the desiredheteroaryl carboxylic acid (Compound 6) and a suitable coupling agent,such as 3-ethyl-1-(3-dimethylaminopropy-1)-3-ethylcarbodiimidehydrochloride (EDCl) or 1,3-dicyclohexylcarbodiimid-e (DCC), at atemperature of 5 to 70° C., for a period of 1 to 24 hours.

After removing the residual solvent, the intermediate amide is treatedwith an excess of an aqueous basic solution, such as sodium hydroxide orpotassium hydroxide at a temperature of 30 to 100° C. for 15 minutes to12 hours to afford the desired8-(carboxymethoxy-heteroaryl)-1,3-disubstituted-xanthine (Compound 7).

Condensation of the intermediate xanthine (Compound 7) with a suitableaniline, or heteroaromatic amine (Compound 8) affords the desiredproducts following normal purification procedures. This condensation istypically performed in dimethylformamide, or other suitable solvent,such as dimethylacetamide, hexamethylphosphortriamide, or ethyl acetate,using EDCl and HOBt to promote the amide bond formation at temperaturesof 10 to 90° C. for periods of 10 minutes to 24 hours.

It will be recognized that a variety of other condensation procedures,all well known in the art, such as the use of DCC or the conversion ofthe carboxylic acid to an activated ester and displacement with theamine, will also result in the preparation of the desired compounds.

In another illustrative synthesis example, Scheme 3, the intermediateCompound 4, dissolved in an appropriate solvent such as anhydrous1,4-dioxane, methylene chloride, 1,2-dichloroethane, or1,2-dimethoxyethane, is treated with a suitable isocyanate (Compound 9)at room temperature or above for a period of 4 to 24 hours to afford thedesired 8-heteroaryl)xanthine ureas. The desired products are typicallyprecipitated by the addition of water, followed by column chromatographypurification on silica gel.

5,6-Diamino-1,3-dimethyluracil, 5,6-diamino-1,3-diallyluracil, and5,6-diamino-1,3-diropylluracil are commercially available. The5,6-diamino-1,3-diisobutyluracil may be prepared as previously described(M. Merlos, et al., Eur. J. Med. Chem. 25: 652 (1990).). The synthesisof 1-methyl-3-benzyloxy-carbonylamino-pyrazole-5-carboxylic acid and1-methyl-5-benzyloxycarbonylamino-pyrazole-3-carboxylic acid follows themethod of Lee and Cain (J. Org. Chem. 54: 428 (1989)).

The synthesis of ethyl (3-carboxy-1-methylpyrazol-5-yl)oxyacetic acidand ethyl (5-carboxy-1-methylpyrazol-3-yl)oxyacetic acid has beendescribed by Sucrow and coworkers (Chem. Ber. 109: 253 (1976) and Chem.Ber. 109: 268 (1976)). 1-Methyl4-nitroimidazole-2-carboxylate isprepared as described by Krowicki and Lown (J. Org. Chem. 52: 3493(1987)). 1-Methyl-4-nitropyrrole-2-carboxylate is commerciallyavailable. Aicher and coworkers (J. Med. Chem. 41: 4556 (1998)) recentlydescribed the preparation of 3-substituted-5-hydroxymethyl-isoxazoles,which are readily acylated using methods well known to those skilled inthe art.

The 4-(substituted)-benzyloxyphenylacetic acids not commerciallyavailable may be prepared from methyl 4-hydroxyphenylacetate and theappropriate benzyl halides, as described by Muller, Reindl, and Breu (J.Med. Chem. 44: 814 (2001)) for 4-(3-methoxybenzyloxy)phenylacetic acid.All other starting materials are generally available from normalcommercial sources.

The following examples are provided in a non-limiting manner to furtherillustrate the methods of synthesis and use of the compounds of thepresent invention.

EXAMPLE 1 Preparation Of Compound AS3

A solution of 1,3-dipropyl-5,6-diaminouracil (0.7 g, 0.003 mol),1-methyl-3-(benzyloxycarbonylamino)-pyrazole-5-carboxylic acid (0.8 g,0.003 mol), and EDCl (0.6 g, 0.003 mol) in 50 mL of CH₃OH was stirred atroom temperature for two hours. Excess CH₃OH was evaporated in vacuo togive a yellow solid that was collected by filtration and washed with H₂Oto give the amide intermediate.

A mixture of the amide intermediate and 30 mL of 2.5 N NaOH was warmedto 70-80° C. for three hours. The clear aqueous solution was cooled andacidified to pH 5 with concentrated HCl. The white precipitate thatformed was collected by filtration and washed with H₂O to afford thedesired 1,3-dipropyl-8-(3-amino-i-methylpyrazol-5-yl)xanthine, which wasrecrystallized from CH₃OH.

MP: 285-288° C.; .¹H-NMR (DMSO-d₆): δ0.93 (m, 6H), 1.58 (m, 2H), 1.75(m, 2H), 3.88 (bs, 2H), 4.01 (s, 5H), 6.21 (s, 1H), 13.51 (bs, 1H).

EXAMPLE 2 Preparation of Compound AS11

A solution of phenylacetic acid (0.196 mmol) in 3 mL of thionyl chloridewas stirred at 70° C. for four hours, then excess thionyl chlorideremoved in a nitrogen stream. A solution of1,3-dipropyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine (0.151 mmol,Example 1) and 0.04 mL of anhydrous triethylamine in 10 mL of CH₂Cl₂:CH₃OH (1:1) was added and the mixture was stirred at room temperaturefor 24 hours, monitoring by TLC.

At completion, the solvent was evaporated, the residue dissolved inethyl acetate, and the solution washed with saturated aqueous NaHCO₃ andbrine. The organic layer was dried (Na₂SO₄), filtered, and evaporated invacuo. The desired product was purified by column chromatography onsilica gel.

MP: 139-140° C.; ¹H-NMR (DMSO-d₆): δ 0.89 (q, 6H, J=5.18 Hz), 1.59 (q,2H), J=7.18 Hz), 1.72 (q, 2H, J=7.06 Hz), 3.62 (s, 2H), 3.88 (t, 2H,J=6.72 Hz), 3.98 (t, 2H), J=6.96 Hz), 4.12 (s, 3H), 7.25-7.33 (m, 6H),10.8 (s, 1H), 14.02 (s, 1H).

EXAMPLE 3 Preparation of Compound AS12

Using 2,4-dichlorophenoxyacetic acid and1,3-dipropyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine (Example 1,Compound AS3).

MP: 225-226° C.; .¹H-NMR (DMSO-d₆): δ 0.85 (m, 6H), 1.59 (m, 2H), 1.72(m, 2H), 3.85 (t, 2H), 4.01 (t, 2H), 4.14 (s, 3H), 4.87 (s, 2H), 7.10(d, 1H), 7.33 (m, 2H), 7.60 (d, 1H), 10.80 (s, 1H), 14.02 (s, 1H).

EXAMPLE 4 Preparation of Compound AS13

Using 3-methoxyphenylacetic acid and1,3-dipropyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine (Example 1,Compound AS3).

MP: 158-159° C.; .¹H-NMR (DMSO-d₆): δ 0.89 (q, 6H, J=7.13 Hz), 1.62 (q,2H), 1.72 (q, 2H), 3.59 (s, 2H), 3.74 (s, 3H), 3.85 (t, 2H), 4.00 (t,2H), 4.13 (s, 3H), 6.92 (s, 1H), 7.30 (m, 4H), 10.77 (s, 1H), 14.00 (s,1H).

EXAMPLE 5 Preparation of Compound AS14

Using 4-(2-methylpropyl)phenylacetic acid and1,3-dipropyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine (Example 1,Compound AS3).

MP: 124-126° C.; .¹H-NMR (DMSO-d₆): δ 0.85 (m, 12H, J=6.52 Hz), 1.39 (d,2H, J=6.87 Hz), 1.75 (m, 5H), 2.41 (d, 2H, J=7.1 Hz), 3.85 (t, 2H,J=6.94 Hz), 4.00 (t, 2H), 4.10 (s, 3H), 7.11 (d, 1H), 7.30 (m, 4H,J=8.05 Hz), 10.70 (s, 1H), 13.99 (s, 1H).

EXAMPLE 6 Preparation of Compound AS15

Using 4-nitrophenylacetic acid and1,3-dipropyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine (Example 1,Compound AS3).

MP: 285-287° C.; .¹H-NMR (DMSO-d₆): δ 0.89 (m, 6H, J=6.83 Hz), 1.55 (q,2H, J=6.83 Hz), 1.72 (q, 2H, J=7.05 Hz), 3.89 (d, 4H), 4.00 (t, 2H),4.13 (s, 3H), 7.27 (s, 1H), 7:63 (d, 2H, J=8.47 Hz), 8.18 (d, 2H, J=8.34Hz), 10.87 (s, 1H), 13.90 (s, 1H).

EXAMPLE 7 Preparation of Compound AS16

Using 4-(benzyloxy)phenylacetic acid and1,3-dipropyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine (Example 1,Compound AS3).

MP: 184-185° C.; .¹H-NMR (DMSO-d₆): δ 0.89 (m, 6H), 1.59 (q, 2H, J=6.98Hz), 1.69 (q, 2H, J=7.1 Hz), 3.54 (s, 2H), 3.85 (t, 2H), 3.98 (t, 2H),4.13 (s, 3H), 5.00 (s, 2H), 6.98 (d, 1H), 7.28 (m, 9H, J=6.46 Hz), 10.75(s,1H), 14.02 (s, 1H).

EXAMPLE 8 Preparation of Compound AS17

Using 4-hydroxyphenylacetic acid and1,3-dipropyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine (Example 1,Compound AS 3).

MP: 145-150° C.; .¹H-NMR (DMSO-d₆): δ 0.86 (m, 6H), 1.55 (m, 2H), 1.72(m, 2H), 3.40 (s, 2H), 3.85 (t, 2H), 3.98 (t, 2H), 4.10 (s, 311), 6.69(d, 2H, J=8), 7.31 (s, 1H), 9.20 (s,1H), 10.70 (s, 1H), 14.0 (s, 1H1).

EXAMPLE 9 Preparation of Compound AS18

Using (S)-2-phenylpropanoic acid and1,3-dipropyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine (Example 1,Compound AS3).

MP: 125-126° C.; .¹H-NMR (CDCl₃): δ 0.85 (m, 6H), 1.57 (s,3H), 1.59 (m,2H), 1.61 (m, 2H), 1.70 (m, 1H), 4.1 (m, 4H), 4.16 (s, 3H), 7.37 (m,5H), 7.39 (s, 1H), 7.90 , (s, 1H), 12.8(s, 1H).

EXAMPLE 10 Preparation of Compound AS19

Using (R)-2-phenylpropanoic acid and1,3-dipropyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine (Example 1,Compound AS3).

MP: 125-126° C.; 1H-NMR (CDCl₃): δ 0.85 (m, 6H), 1.57 (s, 3H), 1.59 (m,2H), 1.61 (m, 2H), 1.70 (m, 1H), 4.1 (m, 4H), 4.16 (s, 3H), 7.37 (m,5H), 7.39 (s, 1H), 7.90 (s, 1H), 12.8 (s, 1H).

EXAMPLE 11 Preparation of Compound AS21

Using 4-chlorophenoxyacetic acid and1,3-dipropyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine (Example 1,Compound AS3).

MP: 260-261° C.; .¹H-NMR (DMSO-d₆): δ 0.85 (m, 6H), 1.59 (m, 2H), 1.72(m, 2H), 3.85 (t, 2H), 3.98 (t, 2H), 4.14 (s, 3H), 6.98 (d, 2H, J=8.0Hz), 7.36 (d, 2H, J=8.0 Hz), 7.33 (s, 1H), 10.80 (s, 1H), 14.02 (s, 1H).

EXAMPLE 12 Preparation of Compound AS22

Using 4-fluorophenylacetic acid and1,3-dipropyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine (Example 1,Compound AS3).

MP: 176° C.; .¹H-NMR (DMSO-d₆). δ 0.88 (m, 6H), 1.60 (m, 2H), 1.70 (m,2H), 3.60 (s, 2H), 3.70 (s, 3H), 3.80 (t, 2H), 4.00 (t, 2H), 4.10 (s,3H), 7.15 (m, 2H), 7.31 (m, 2H), 7.30 (s, 1H), 10.70 (s, 1H), 14.0 (s,1H).

EXAMPLE 13 Preparation of Compound AS23

Using 4-methoxyphenylacetic acid and1,3-dipropyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine (Example 1,Compound AS3).

MP: 125-126° C.; .¹H-NMR (DMSO-d₆): δ 0.86 (m, 6H), 1.50 (m, 2H), 1.70(m, 2H), 3.50 (s, 2H), 3.70 (s, 3H), 3.80 (t, 2H), 4.00 (t, 2H), 4.10(s, 3H), 7.15 (m, 2H), 7.31 (m, 2H), 7.30 (s, 1H), 10.70 (s, 1H), 14.0(s, 1H).

EXAMPLE 14 Preparation of Compound AS24

Using 3-chlorophenylacetic acid and1,3-dipropyl-8-(3-amino-i1-methypyrazol-5-yl)xanthine (Example 1,Compound AS3).

MP: 143-145 ° C.; ¹H-NMR (DMSO-d₆): δ 0.86 (m, 611), 1.50 (m, 2H), 1.70(m, 2H), 3.60 (s, 2H), 3.80 (t, 2H), 4.00 (t, 2H), 4.10 (s, 3H), 7.30(m, 4H), (s, 1H), 10.8 (s, 1H), 14.0 (s, 1H).

EXAMPLE 15 Preparation of Compound AS25

Using 3-fluorophenylacetic acid and1,3-dipropyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine (Example 1,Compound AS3).

MP: 148-150° C.; .¹H-NMR (DMSO-d₆): δ 0.86 (m, 6H), 1.50 (m, 2H), 1.70(m, 2H), 3.60 (s, 2H), 3.80 (t, 2H), 4.00 (t, 2H), 4.10 (s, 3H), 7.10(m, 4H), 7.30 (s, 1H), 10.8 (s, 1H), 14.0 (s, 1H).

EXAMPLE 16 Preparation of Compound AS26

Using 4-(dimethylamino)phenylacetic acid and1,3-dipropyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine (Example 1,Compound AS3).

MP: 215° C.; .¹H-NMR (DMSO-d₆): δ 0.86 (m, 6H), 1.50 (m, 2H), 1.70 (m,2H), 2.80 (s, 6H), 3.60 (s, 2H), 3.80 (t, 2H)?, 4.00 (t, 2H), 4.10 (s,3H), 6.67 (d, 2H, J=8.0 Hz), 7.14 (d, 2H, J=8.0 Hz), 7.29 (s, 1H), 10.8(s, 1H), 14.0 (s, 1H).

EXAMPLE 17 Preparation of Compound AS27

Using 4-chlorophenylacetic acid and1,3-dipropyl-8-(3-amino-1-methy-1pyrazol-5-yl)xanthine (Example 1,Compound AS3).

MP: 159-161° C.; ¹H-NMR (DMSO-d₆): δ 0.86 (m, 6H), 1.50 (m, 2H), 1.70(m, 2H), 3.60 (s, 2H), 3.80 (t, 2H), 4.00 (t, 2H), 4.10 (s, 3H), 7.29(s, 1H), 7.32 (d, 2H, J=8.0 Hz), 7.38 (d, 2H, J=8.0 Hz), 10.8 (s, 1H),14.0 (s, 1H).

EXAMPLE 18 Preparation of Compound AS28

Using 3,4-(dimethoxy)phenylacetic acid and1,3-dipropyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine (Example 1,Compound AS3).

MP: 140-142° C.; ¹H-NMR (DMSO-d₆): δ 0.87 (m, 6H), 1.55 (q, 2H), 1.72(q, 2H), 3.50 (s, 2H), 3.74 (s, 6H), 3.82 (t, 2H), 4.02 (t, 2H), 4.13(s, 3H), 6.88 (m, 3H, J=3.58). 6.96 (d, 1H), 7.33 (s, 1H), 10.73 (s,1H).

EXAMPLE 19 Preparation of Compound AS29

Using 4-(2-trifluoromethylbenzyloxy)phenylacetic acid and1,3-dipropyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine (Example 1,Compound AS3).

MP: 184-186° C.; .¹H-NMR (DMSO-d₆): δ 0.88 (m, 6H), 1.59 (q, 2H), 1.69(q, 2H), 3.54 (s, 2H), 3.85 (t, 2H), 4.00 (t, 2H), 4.12 (s, 3H), 5.20(s, 2H), 6.92 (d, 1H), 7.28 (m, 3H, J=5.48), 7.73 (m, 4H, J=6.55), 10.75(s, 1H), 14.02 (s, 1H).

EXAMPLE 20 Preparation of Compound AS30

Using 4-(3-trifluoromethylbenzyloxy)phenylacetic acid and1,3-dipropyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine (Example 1,Compound AS3).

MP: 218-220° C.; ¹H-NMR (DMSO-d₆): δ 0.88 (m, 6H, J=5.06), 1.55 (q, 2H,J=6.88), 1.72 (q, 2H, J=7.47), 3.55 (s, 2H), 4.01 (t, 2H), 4.08 (t, 2H),4.12 (s, 3H), 5.20 (s, 2H), 5.76 (s, 1H), 7.00 (d, 1H), 7.68 (t, 3H),7.80 (m, 4H), 10.75 (s, 1H), 14.01 (s, 1H).

EXAMPLE 21 Preparation of Compound AS31

Using 4-(4-nitrobenzyloxy)phenylacetic acid and1,3-dipropyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine (Example 1,Compound AS3).

MP: 136-139° C.; .¹H-NMR (DMSO-d₆): δ 0.88 (m, 6H), 1.55 (q, 2H), 1.72(q, 2H), 3.55 (s, 2H), 4.01 (t, 2H), 4.08 (t, 2H), 4.12 (s, 3H), 5.20(s, 2H), 7.00 (d, 1H), 7.48 (t, 4H), 7.80 (d, 2H), 8.30 (d, 2H), 10.75(s, 1H).

EXAMPLE 22 Preparation of Compound AS32

Using 4-(trifluoromethyl)phenylacetic acid and1,3-dipropyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine (Example 1,Compound AS3).

MP: 240° C.; .¹H-NMR (DMSO-d₆): δ 0.88 (m, 6H), 1.55 (q, 2H), 1.72 (q,2H), 3.75 (s, 2H), 3.89 (t, 2H), 4.01 (t, 2H), 4.08 (s, 3H), 7.27 (s,1H), 7.68 (d, 2H), 7.80 (d, 2H), 10.85 (s, 1H).

EXAMPLE 23 Preparation of Compound AS43

Using 3,4-difluorophenylacetic acid and1,3-dipropyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine (Example 1,Compound AS3).

MP: 250-252° C.;. ¹H-NMR (DMSO-d₆): δ 0.86 (m, 6H), 1.50 (m, 2H), 1.70(m, 2H), 3.60 (s, 2H), 3.80 (t, 2H), 4.00 (t, 2H), 4.10 (s, 3H), 7.29(s, 1H), 7.32 (m, 3H), 10.80 (s, 1H), 14.00 (s, 1H).

EXAMPLE 24 Preparation of Compound AS44

Using 3,4,5-(trimethoxy)phenylacetic acid and1,3-dipropyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine (Example 1,Compound AS3).

MP: 298-300° C.; ¹H-NMR (DMSO-d₆): δ 0.88 (m, 6H), 1.55 (q, 2H), 1.72(q, 2H), 3.54 (s, 2H), 3.62 (s, 3H), 3.75 (s, 6H), 3.85 (t, 2H), 4.01(t, 2H), 4.13 (s, 3H), 6.66 (s, 2H), 7.33 (s, 1H), 10.74 (s, 1H), 14.01(s, 1H).

EXAMPLE 25 Preparation of Compound AS56

Using 4-(benzyloxy)-3-methoxyphenylacetic acid and1,3-dipropyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine (Example 1,Compound AS3).

MP: 205-208° C.; ¹H-NMR (DMSO-d₆): δ 0.89 (m, 6H), 1.55 (m, 2H), 1.72(m, 2H), 3.54 (s, 2H), 3.76 (s, 3H), 3.85 (t, 2H), 4.01 (t, 2H), 4.13(s, 3H), 5.04 (s, 2H), 6.84 (d, 1H), 6.98 (d, 2H), 7.38 (m, 6H, J=8.36),10.72 (s, 1H).

EXAMPLE 26 Preparation of Compound AS57

Using 3,4-methylenedioxyphenylacetic acid and1,3-dipropyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine (Example 1,Compound AS3).

MP: 138-140° C.; ¹H-NMR (DMSO-d₆): δ 0.88 (m, 6H), 1.58 (m, 2H), 1.71(m, 2H), 3.52 (s, 2H), 3.85 (t, 2H), 4.00 (t, 2H), 4.12 (s, 3H), 5.97(s, 2H), 6.83 (m, 3H), 7.27 (s, 1H), 10.71 (s, 1H), 14.00 (s, 1H).

EXAMPLE 27 Preparation of Compound AS58

Using 4-hydroxy-3-methoxyphenylacetic acid and1,3-dipropyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine (Example 1,Compound AS3).

MP: 185° ° C.; ¹H-NMR (DMSO-d₆): δ 0.88 (m, 6H), 1.58 (m, 2H), 1.71 (m,2H), 3.40 (s, 2H), 3.81 (s, 3H), 3.83 (t, 2H), 3.88 (t, 2H), 4.12 (s,3H), 6.70 (s, 1H), 6.90 (s, 1H), 7.30 (s, 1H), 8.80 (s, 1H), 10.71 (s,1H), 14.00 (s, 1H).

EXAMPLE 28 Preparation of Compound AS8

A solution of succinic anhydride and1,3-dipropyl-8-(3-amino-1-meth-ylpyrazol-5-yl)xanthine (Example 1,Compound AS3) in 1,4-dioxane was heated at 60 OC overnight, the solventremoved, and the residue purified by column chromatography on silica gelto provide the desired product.

MP: 265-266° C.; ¹H-NMR (DMSO-d₆): δ 0.86 (m, 6H), 1.55 (m, 2H), 1.72(m, 2H), 3.31 (s, 2H), 3.34 (s, 2H), 3.65 (t, 2H), 3.98 (t, 2H), 4.01(s, 3H), 7.33 (s, 1H), 10.50 (s, 1H), 12.10 (s, 1H), 14.01 (s, 1H).

EXAMPLE 29 Preparation of Compound AS9

Using 4-(t-butyloxycarbonylamino)butanoic acid and1,3-dipropyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine (Example 1,Compound AS3).

MP: 215-216° C.; ¹H-NMR (DMSO-d₆): δ 0.89 (m, 6H), 1.37 (s, 9H), 1.66(m, 6H), 2.28 (m, 2H), 2.91 (m, 2H), 3.86 (t, 2H), 4.01 (t, 2H), 4.12(s, 3H), 7.30 (s, 1H), 10.50 (s, 1H), 14.01 (s, 1H).

EXAMPLE 30 Preparation of Compound AS10

A solution of1,3-dipropyl-8-(3-(4-(t-butyloxycarbonylamino)-1-oxo-butylamino)-1-methyl-pyrazol-5-yl)xanthine(Example 29) in 1,4-dioxane was treated with excess ethereal HCl (2 N)at room temperature for 16 hours, during which a white solidprecipitated. This was collected by filtration, washing with diethylether to afford the desired product as the hydrochloride salt.

MP: 251-252° C.; ¹H-NMR (DMSO-d₆): δ 0.89 (m, 6H), 1.59 (m, 2H), 1.72(m, 4H), 2.45 (m, 2H), 2.81 (t, 2H), 3.86 (t, 2H), 3.98 (t, 2H), 4.12(s, 3H), 7.30 (s, 1H), 7.95 (s, 3H), 10.62 (s, 1H), 14.02 (s, 1H).

EXAMPLE 31 Preparation of Compound AS38

A solution of 1,3-dimethyl-5,6-diaminouracil (0.7 g, 0.003 mol),1-methyl-3-(benzyloxycarbonylamino)-pyrazole-5-carboxylic acid (0.8 g,0.003 mol), and EDCl (0.6 g, 0.003 mol) in 50 mL of CH₃OH was stirred atroom temperature for two hours. Excess CH₃OH was evaporated in vacuo togive a yellow solid that was collected by filtration and washed with H₂Oto give the amide intermediate.

A mixture of the amide intermediate and 30 mL of 2.5 N NaOH was warmedto 70-80° C. for three hours. The clear aqueous solution was cooled andacidified to pH 5 with concentrated HCl. The white precipitate thatformed was collected by filtration and washed with H₂O to afford thedesired 1,3-dimethyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine, which wasrecrystallized from CH₃OH.

MP: >300° C.; ¹H-NMR (DMSO-d₆): δ 3.20 (s, 3H), 3.40 (s, 3H), 4.00 (s,3H), 5.50 (s, 2H), 6.20 (s, 1H), 13.20 (s, 1H).

EXAMPLE 32 Preparation of Compound AS40

Using phenylacetic acid and1,3-dimethyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine (Example 31).

MP: >300° C.; ¹H-NMR (DMSO-d₆): δ 3.20 (s, 3H), 3.40 (s, 3H), 3.60 (s,2H), 4.10 (s, 3H), 7.30 (s, 1H), 7.40 (m, 5H), 10.80 (s, 1H), 14.00 (s,1H).

EXAMPLE 33 Preparation of Compound AS7

A solution of 1,3-dipropyl-5,6-diaminouracil (0.7 g, 0.003 mol),1-methyl-4-nitropyrrole-2-carboxylic acid (0.8 g, 0.003 mol), and EDCl(0.6 g, 0.003 mol) in 50 mL of CH₃OH was stirred at room temperature fortwo hours. Excess CH₃OH was evaporated in vacuo to give a yellow solidthat was collected by filtration and washed with H₂O to give the amideintermediate.

A mixture of the amide intermediate and 30 mL of 2.5 N NaOH was warmedto 70-80° C. for three hours. The clear aqueous solution was cooled andacidified to pH 5 with concentrated HCl. The white precipitate thatformed was collected by filtration and washed with H₂O to afford thedesired 1,3-dipropyl-8-(1-methyl-4-nitropyrrol-2-y-1)xanthine, which wasrecrystallized from CH₃OH.

MP: 295-297° C.; ¹H-NMR (DMSO-d₆): δ 0.86 (m, 6H), 1.55 (m, 2H), 1.72(m, 2H), 3.88 (t, 2H), 3.98 (t, 2H), 3.99 (s, 3H), 7.52 (s, 1H), 8.20(s, 1H), 14.00 (s, 1H).

EXAMPLE 34 Preparation of Compound AS36

Using 1,3-dipropyl-5,6-diaminouracil and1-methyl-4-nitroimidazole-2-carboxylic acid.

EXAMPLE 35 Preparation of Compound AS33

Using 1,3-dipropyl-5,6-diaminouracil and3-(2-ethoxycarbonyl-1-meth-ylpyrrol-4-yl)acrylic acid.

MP: 210-211° C.; ¹H-NMR (DMSO-d₆): δ 0.85 (m, 6H), 1.30 (t, 3H), 1.59(m, 2H), 1.72 (m, 2H), 3.85 (s, 3 H), 4.03 (s, 3 H), 4.10 (q, 2H), 7.10(d, 2H), 7.59 (d, 2H), 7.60 (s, 1H).

EXAMPLE 36 Preparation of Compound AS59

To a solution of ethyl (5-carboxy-1-methylpyrazol-3-yl)oxyacetic acid(0.5 mmol) and EDCl (0.5 mmol) in methanol (20 mL) was added a solutionof 1,3-dipropyl-5,6-diaminouracil (0.5 mmol), dissolved in methanol (20mL). The mixture was stirred at room temperature for two hours, thesolvent was then removed in vacuo, water added, and the solid thatformed was collected by filtration and washed with additional coldwater. The intermediate amide was heated in 20 mL of 2.5 N NaOH at 70°C. for 30 minutes to afford the desired2-[5-(1,3-dipropyl-xanthin-8-yl)-1-methyl-pyrazol-3-yl)oxyacetic acid.

Condensation of2-[5-(1,3-dipropyl-xanthin-8-yl)-1-methyl-pyrazol-3-yl)oxyacetic acid(0.5 mmol) and 5-methyl-2-aminopyridine (1.3 mmol) in the presence ofEDCl (1.12 mmol) and HOBt (1.14 mmol) in anhydrous dimethylformamideafforded the desired product.

MP: 278-280° C.; ¹H-NMR (DMSO-d₆): δ 0.90 (m, 6H, J=4.66 Hz), 1.55 (m,2H, J=7.38 Hz), 1.67 (m, 2H, J=7.34 Hz), 2.24 (s, 3H), 3.89 (t, 2H,J=7.34 Hz), 4.00 (t, 2H), J=7.14 Hz), 4.05 (s, 3H), 4.82 (s, 2H), 6.44(s, 1H), 7.64 (dd, 1H), 7.93 (d, 1H), 8.15 (d, 1H), 10.43 (s, 1H), 13.95(bs, 1H).

EXAMPLE 37 Preparation of Compound AS64

Using 4-fluoroaniline and2-[5-(1,3-dipropyl-xanthin-8-yl)-1-methyl-pyrazol-3-yl)oxyacetic acid(Example 36).

MP: 264° C.; 1H-NMR (DMSO-d₆): δ 0.87 (m, 6H), 1.55 (q, 2H), 1.59 (q,2H), 3.86 (t, 2H), 4.00 (t, 2H), 4.07 (s, 3H), 4.76 (s, 2H), 6.50 (s,1H), 7.16 (m, 2H, J=8.75 Hz), 7.64 (m, 2H, J=5.04), 10.20 (s, 1H).

EXAMPLE 38 Preparation of Compound AS65

Using 4-bromoaniline and2-[5-(1,3-dipropyl-xanthin-8-yl)-1-methyl-pyrazol-3-yl)oxyacetic acid(Example 36).

MP: 264° C.; ¹H-NMR (DMSO-d₆): δ 0.90 (m, 6H), 1.59 (m, 2H), 1.71 (m,2H), 3.86 (t, 2H), 4.00 (t, 2H), 4.06 (s, 3H), 4.77 (s, 2H), 6.50 (s,1H), 7.52 (m, 4H), 10.26 (s, 1H).

EXAMPLE 39 Preparation of Compound AS68

Using 3,4-methylenedioxyaniline and2-[5-(1,3-dipropyl-xanthin-8-yl-)-1-methyl-pyrazol-3-yl)oxyacetic acid(Example 36).

MP: 272-273° C.; ¹H-NMR (DMSO-d₆): δ 0.89 (m, 6H), 1.60 (m, 2H), 1.70(m, 2H), 3.90 (t, 2H), 3.98 (t, 2H), 4.07 (s, 3H), 4.73 (s, 2H), 5.98(s, 2H), 6.52 (s, 1H), 6.88 (d, 1H, J=8.44 Hz), 7.01 (d, 1H), 7.32 (s,1H), 10.01 (s, 1H).

EXAMPLE 40 Preparation of Compound AS69

Using 4-acetylaniline and 2-[5-(1,3-dipropyl-xanthin-8-yl)-1-methyl-pyrazol-3-yl)oxyacetic acid (Example36).

MP: 273-275° C.; ¹H-NMR (DMSO-d₆): δ 0.90 (m, 61H, J=7.34Hz), 1.74 (m,4H, J=6.97 Hz), 2.60 (s, 3H), 4.00 (bt, 2H), 4.14 (t, 2H), 4.19 (s, 3H),4.86 (s, 2H), 6.60 (s, 1H), 7.85 (d, 2H, J=8.58 Hz), 7.96 (d, 2H,J=8.69Hz), 8.82 (s, 1H), 12.95 (bs, 1H).

EXAMPLE 41 Preparation of Compound AS66

To a solution of ethyl (5-carboxy-1-methylpyrazol-3-yl)oxyacetic acid(0.5 mmol) and EDCl (0.5 mmol) in methanol (20 mL) was added a solutionof 1,3-diisobutyl-5,6-diaminouracil (0.5 mmol), dissolved in methanol(20 mL). The mixture was stirred at room temperature for two hours, thesolvent was then removed in vacuo, water added, and the solid thatformed was collected by filtration and washed with additional coldwater. The intermediate amide was heated in 20 mL of 2.5 N NaOH at 70°C. for 30 minutes to afford the desired2-[5-(1,3-diisobutyl-xanthin-8-yl)-1-methyl-pyrazol-3-yl)oxyacetic acid.

Condensation of2-[5-(1,3-diisobutyl-xanthin-8-yl)-1-methyl-pyrazol-3-yl)oxyacetic acid(0.5 mmol) and 4-fluoroaniline (1.3 mmol) in the presence of EDCl (1.12mmol) and HOBt (1.14 mmol) in anhydrous dimethylformamide afforded thedesired product.

MP: 227-230° C.; ¹H-NMR (DMSO-d₆): δ 0.87 (t, 12H, J=7.58Hz), 2.05 (bm,2H), 3.74 (d, 2H, J=7.15 Hz), 3.85 (d, 2H, J=7.15), 4.06 (s, 2H), 4.76(s, 2H), 6.51 (s, 1H), 7.16 (t, 2H), 7.64 (m, 2H), 10.17 (s, 1H), 13.96(bs, 1H).

EXAMPLE 42 Preparation of Compound AS67

Condensation of2-[5-(1,3-diisobutyl-xanthin-8-yl)-1-methyl-pyrazol-3-yl)oxyacetic acid(Example 44, Compound AS35, 0.5 mmol) and 4-bromoaniline (1.3 mmol) inthe presence of EDCl (1.12 mmol) and HOBt (1.14 mmol) in anhydrousdimethylformamide afforded the desired product.

MP: 258-260° C.; ¹H-NMR (DMSO-d₆): δ 0.87 (t, 12H, J=7.22Hz), 2.06 (m,2H), 3.77 (d, 2H, J=7.3 Hz), 3.85 (d, 2H, J=7.16), 4.06 (s, 3H), 4.77(s, 2H), 6.51 (s, 1H), 7.52 (dd, 4H, J=8.88 Hz), 10.26 (s, 1H), 13.96(s, 1H).

EXAMPLE 43 Preparation of Compound AS37

A solution of 1,3-dipropyl-5,6-diaminouracil (0.7 g, 0.003 mol),1-methyl-5-(benzyloxycarbonylamino)-pyrazole-3-carboxylic acid (0.8 g,0.003 mol), and EDCl (0.6 g, 0.003 mol) in 50 mL of CH₃OH was stirred atroom temperature for two hours. Excess CH₃OH was evaporated in vacuo togive a yellow solid that was collected by filtration and washed with H₂Oto give the amide intermediate.

A mixture of the amide intermediate and 30 mL of 2.5 N NaOH was warmedto 70-80° C. for three hours. The clear aqueous solution was cooled andacidified to pH 5 with concentrated HCl. The white precipitate thatformed was collected by filtration and washed with H₂O to afford thedesired 1,3-dipropyl-8-(5-amino-1-methylpyrazol-3-yl)xanthine, which wasrecrystallized from CH₃OH.

MP: 249-250° C.; ¹H-NMR (DMSO-d₆): δ 0.85 (m, 6H), 1.59 (m, 2H), 1.72(m, 2H), 3.50 (s, 3H), 3.85 (m, 2H), 3.95 (m, 2H), 5.50 (d, 2H), 6.00(s,1H), 13.50 (s, 1H),

EXAMPLE 44 Preparation of Compound AS35

A solution of phenylacetic acid (0.196 mmol) in 3 mL of thionyl chloridewas stirred at 70° C. for four hours, then excess thionyl chlorideremoved in a nitrogen stream. A solution of1,3-dipropyl-8-(5-amino-1-methylpyrazol-3-yl)xanthine (0.151 mmol,Example 43) and 0.04 mL of anhydrous triethylamine in 10 mL of CH₂Cl₂:CH₃OH (1:1) was added and the mixture was stirred at room temperaturefor 24 hours, monitoring by TLC.

At completion, the solvent was evaporated, the residue dissolved inethyl acetate, and the solution washed with saturated aqueous NaHCO₃ andbrine. The organic layer was dried (Na₂SO₄), filtered, and evaporated invacuo. The desired product was purified by column chromatography onsilica gel.

MP: 279-281° C.; ¹H-NMR (DMSO-d₆): δ 0.88 (m, 6H), 1.55 (m, 2H), 1.72(m, 2H), 3.60 (s, 3H), 3.75 (s, 2H), 3.89 (t, 2H), 4.01 (t, 2H), 7.27(s, 1H), 6.90 (s, 1H), 7.20 (m, 5H), 10.20 (s, 1H), 14.00 (s, 1H).

EXAMPLE 45 Preparation of Compound AS60

To a solution of ethyl (3-carboxy-1-methylpyrazol-5-yl)oxyacetic acid(0.5 mmol) and EDCl (0.5 mmol) in methanol (20 mL) was added a solutionof 1,3-dipropyl-5,6-diaminouracil (0.5 mmol), dissolved in methanol (20mL). The mixture was stirred at room temperature for two hours, thesolvent was then removed in vacuo, water added, and the solid thatformed was collected by filtration and washed with additional coldwater. The intermediate amide was heated in 20 mL of 2.5 N NaOH at 70°C. for 30 minutes to afford the desired3-[5-(1,3-dipropyl-xanthin-8-yl)-1-methyl-pyrazol-5-yl)oxyacetic acid.

Condensation of3-[5-(1,3-dipropyl-xanthin-8-yl)-1-methyl-pyrazol-5-yl)oxyacetic acid(0.5 mmol) and 4-bromoaniline (1.3 mmol) in the presence of EDCl (1.12mmol) and HOBt (1.14 mmol) in anhydrous dimethylformamide afforded thedesired product.

MP: 242° C.; ¹H-NMR (DMSO-d₆): δ 0.88 (m, 6H), 1.70 (m, 4H), 3.70 (s,3H), 3.85 (t, 2H), 3.98 (t, 2H), 4.85 (s, 2H), 6.32 (s, 1H), 7.62 (dd,4H, J=8 Hz), 10.33 (s, 1H), 13.70 (s, 1H).

EXAMPLE 46 Preparation of Compound AS61

Condensation of3-[5-(1,3-dipropyl-xanthin-8-yl)-1-methyl-pyrazol-5-yl)oxyacetic acid(Example 45, 0.5 mmol) and 4-bromoaniline (1.3 mmol) in the presence ofEDCl (1.12 mmol) and HOBt (1.14 mmol) in anhydrous dimethylformamideafforded the desired product.

MP: 262° C.; ¹H-NMR (DMSO-d₆): δ 0.88 (m, 6H), 1.70 (m, 4H), 3.70 (s,3H), 3.85 (t, 2H), 3.98 (t, 2H), 4.85 (s, 2H), 6.32 (s, 1H), 7.18 (t,2H, J=8.88Hz), 7.62 (m, 2H, J=6.92 Hz), 10.25 (s, 1H), 13.70 (s, 1H).

EXAMPLE 47 Preparation of Compound AS62

To a solution of ethyl (3-carboxy-1-methylpyrazol-5-yl)oxyacetic acid(0.5 mmol) and EDCl (0.5 mmol) in methanol (20 mL) was added a solutionof 1,3-diisobutyl-5,6-diaminouracil (0.5 mmol), dissolved in methanol(20 mL). The mixture was stirred at room temperature for two hours, thesolvent was then removed in vacuo, water added, and the solid thatformed was collected by filtration and washed with additional coldwater. The intermediate amide was heated in 20 mL of 2.5 N NaOH at 70°C. for 30 minutes to afford the desired3-[5-(1,3-diisobutyl-xanthin-8-yl)-1-methyl-pyrazol-5-yl)oxyacetic acid.

Condensation of3-[5-(1,3-bisisobutyl-xanthin-8-yl)-1-methyl-pyrazo-1-5-yl)oxyaceticacid (0.5 mmol) and 4-fluoroaniline (1.3 mmol) in the presence of EDCl(1.12 mmol) and HOBt (1.14 mmol) in anhydrous dimethylformamide affordedthe desired product.

MP: 251-252° C.; ¹H-NMR (DMSO-d₆): δ 0.85 (t, 12H), 2.10 (m, 2H), 3.75(s, 3H), 3.83 (dd, 4H), 4.86 (s, 2H), 6.32 (s, 1H), 7.18 (t, 2H, J=8.85Hz), 7.62 (m, 2H, J=5.03 Hz), 13.70 (s, 1H).

EXAMPLE 48 Preparation of Compound AS63

Condensation of3-[5-(1,3-bisisobutyl-xanthin-8-yl)-1-methyl-pyrazo-1-5-yl)oxyaceticacid (xanthine intermediate from Example 47, 0.5 mmol) and4-bromoaniline (1.3 mmol) in the presence of EDCl (1.12 mmol) and HOBt(1.14 mmol) in anhydrous dimethylformamide afforded the desired product.

MP: 234° C.; ¹H-NMR (DMSO-d₆): δ 0.84 (t, 12H), 2.10 (m, 2H), 3.73 (s,3H), 3.831 (dd, 4H), 4.85 (s, 2H), 6.26 (s, 1H), 7.53 (q, 4H), 10.36 (s,1H), 13.64 (s, 1H).

EXAMPLE 49 Preparation of Compound AS4

A solution of 1,3-dipropyl-5,6-diaminouracil (0.7 g, 0.003 mol),3-(benzoyloxymethyl)-oxazole-5-carboxylic acid (0.8 g, 0.003 mol), andEDCl (0.6 g, 0.003 mol) in 50 mL of CH₃OH was stirred at roomtemperature for two hours. Excess CH₃OH was evaporated in vacuo to givea solid that was collected by filtration and washed with H₂O to affordthe amide intermediate.

A mixture of the amide intermediate and 30 mL of 2.5 N NaOH was warmedto 70-80° C. for three hours. The clear aqueous solution was cooled andacidified to pH 5 with concentrated HCl. The white precipitate thatformed was collected by filtration and washed with H₂O to afford thedesired 1,3-dipropyl-8-[3-(benzoyloxymethyl)-oxazo-1-5-yl]xanthine,which was recrystallized from CH₃OH.

MP: 236-238° C.; ¹H-NMR (DMSO-d₆): δ 0.96 (m, 6H), 1.49 (m, 2H), 1.59(m, 2H), 3.88 (t, 2H), 3.98 (bs, 2H), 5.60 (s, 2H), 7.25 (s, 1H), 7.74(m, 3H), 8.00 (m, 2H), 14.50 (s,1 H).

EXAMPLE 50 Preparation of Compound AS20

Using 1,3-dipropyl-5,6-diaminouracil and3-[3-(benzoyloxymethyl)oxa-zol-5-yl]xanthine, acrylic acid, therequisite intermediate was prepared, as described for Example 41. Theproduct was treated with sodium hydride, followed by methyl iodide inTHF to provide the desired product.

MP: 165° C.; ¹H-NMR (DMSO-d₆): δ 0.85 (m, 6H), 1.59 (m, 2H), 1.72 (m,2H), 3.85 (t, 2H), 3.98 (t, 2H), 4.03 (s, 3H), 5.50 (s, 2H), 7.30 (s,1H), 7.57 (m, 3H), 7.59 (d, 2H, J=8Hz), 8.03 (d, 2H, J=8Hz).

EXAMPLE 51 Preparation of Compound AS53

To a solution of 1,3-dipropyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine(3 mmol, Example 1) in 1,4-dioxane at room temperature was added4-(dimethylaminophenyl)isocyanate (3.2 mmol). The mixture was stirredovernight at room temperature, quenched by the addition of water, andthe precipitated product collected by filtration. Purification wasachieved by column chromatography on silica gel.

MP: 266-268° C.; ¹H-NMR (DMSO-d₆): δ 0.87 (m, 6H), 1.50 (m, 2H), 1.60(m, 2H), 2.80 (s, 6H), 3.83 (m, 2H), 3.98 (m, 2H), 4.10 (s, 3H), 6.69(d, 11H, J=8.0 Hz), 6.94 (d, 1H, J=8.0 Hz), 7.1 (s, 1H), 7.27 (d, 2H,J=8.0 Hz), 8.64 (s, 1H), 8.98 (s, 1H).

EXAMPLE 52 Preparation of Compound AS54

Using 3-chlorophenylisocyanate and1,3-dipropyl-8-(3-amino-1-methyl-pyrazol-5-yl)xanthine (Example 1,Compound AS3).

MP: >300° C.; ¹H-NMR (DMSO-d₆): δ 0.87 (m, 6H), 1.50 (m, 2H), 1.60 (m,2H), 3.83 (m, 2H), 3.98 (m, 2H), 4.10 (s, 3H), 7.01 (m, 1H), 7.19 (s,1H), 7.30 (m, 2H), 7.70 (s, 1H), 9.03 (s, 1H), 9.15 (s, 1H), 14.0 (s,1H).

EXAMPLE 53 Preparation of Compound AS55

Using 3-(methoxy)phenylisocyanate and1,3-dipropyl-8-(3-amino-1-met-hylpyrazol-5-yl)xanthine (Example 1,Compound AS3).

MP: >300° C.; ¹H-NMR (DMSO-d₆): δ 0.87 (m, 6H), 1.50 (m, 2H), 1.60 (m,2H), 3.82 (s, 3H), 3.86 (m, 2H), 3.98 (m,2H), 4.10 (s, 3H), 6.54 (d, 1H,J=8.0 Hz), 6.90 (d, 1H, J=8.0 Hz), 7.10 (s, 1H), 7.24 (m, 2H), 8.90 (s,1H), 9.07 (s, 1H), 14.0 (s, 1H,

EXAMPLE 54 Preparation of Compound AS49

Using 4-(methoxy)phenylisocyanate and1,3-dipropyl-8-(3-amino-1-met-hylpyrazol-5-yl)xanthine (Example 1,Compound AS3).

Yield: 98% MP: >300° C.; 1H NMR (DMSO-d₆): δ 0.80 (m, 6H); 1.62 (m, 2H);1.70 (m, 2H); 3.68 (s, 3H); 3.75 (m, 2H); 4.02 (m, 2H); 4.22 (s, 3H);7.00 (d, 2H, J=8.00 Hz); 7.25 (s, 1H); 7.32 (d, 2H, J=8.00 Hz); 8.82 (s,1H); 8.95 (S, 1H); 14.01 (s, 1H).

EXAMPLE 55 Preparation of Compound AS1

To a solution of 1,3-dipropyl-5,6-diaminouracil (2.2 mmol) in methanol(10 mL) was added an equimolar amount of1-methyl-1H-pyrazole-3,-5-dicarboxylic acid 5-ethyl ester and DCl (2.21mmol). The reaction mixture was stirred at room temperature for 4-5 hwith monitoring by TLC. At completion, the reaction mixture wasconcentrated in vacuo and water added. The intermediate amideprecipitated and was collected by filtration. The solid thus collectedwas dissolved in methanol (10 mL), 2.5 N NaOH (15 mL) added, and themixture heated to 70-80° C. for 12 hours. After removal of the methanol,the residue was taken up in water, acidified to pH 4-5 with HCl, and theresultant precipitate collected by filtration. The desired product waspurified by flash chromatography on silica gel, eluting with ethylacetate/petroleum ether.

Yield: 40%; MP: >300° C.; 1H NMR (DMSO-d₆): δ 0.93 (m, 6H); 1.58 (m,2H), 1.75 (m, 2H); 3.88 (m, 2H); 3.98 (m, 2H); 4.01 (s, 3H); 7.43(s,1H); 13.60 (bs, 2H).

EXAMPLE 56 Preparation of Compound AS91

Using 4-(sec-butyl)aniline and2-[5-(1,3-dipropyl-xanthin-8-yl)-1-m-ethyl-pyrazol-3-yl)oxyacetic acid(Example 36), according to the method described in Example 36.

Yield: 36%; MP: 240-242° C.; 1H NMR (DMSO-d₆): δ 0.74 (t, 3H, J=8.00);0.85 (m, 9H); 1.15 (d, 3H, J=8.00); 1.51 (m, 2H); 1.55 (m, 2H); 3.86 (m,2H); 4.00 (m, 2H); 4.06 (s, 3H); 4.74 (s, 2H); 6.50 (s, 1H); 7.12 (d,2H, J=8.00); 7.52 (d, 2H, J=8.00); 10.02 (s, 1H); 13.93 (s, 1H).

EXAMPLE 57 Preparation of Compound AS92

Using 4-(methyl)aniline and2-[5-(1,3-dipropyl-xanthin-8-yl)-1-meth-yl-pyrazol-3-yl)oxyacetic acid(Example 36), according to the method described in Example 36.

Yield: 38%; MP: 256-257° C.; 1H NMR (DMSO-d₆): δ 0.87 (m, 6H); 1.56 (m,2H); 1.73 (m, 2H); 2.24 (s, 3H); 3.84 (m, 2H); 3.94 (m, 2H); 4.05 (s,3H); 4.74 (s, 2H); 6.51 (s, 1H); 7.12 (d, 2H, J=8.10); 7.50 (d, 2H,J=8.15); 10.01 (s, 1H); 13.94 (s, 1H).

EXAMPLE 58 Preparation of Compound AS93

Using 4-(N-morpholino)aniline and2-[5-(1,3-dipropyl-xanthin-8-yl)-1-methyl-pyrazol-3-yl)oxyacetic acid(Example 36), according to the method described in Example 36.72

Yield: 46%; MP: 296-298° C.; 1H NMR (DMSO-d₆): δ 0.87 (m, 6H); 1.57 (m,2H); 1.75 (m, 2H); 3.03 (m, 4H); 3.71 (m, 4H); 3.74 (m, 2H); 3.85 (m,2H); 4.03 (s, 3H); 4.71 (s, 2H); 6.46 (s, 1H); 6.89 (d, 2H, J=8.27);7.48 (d, 2H, J=8.22); 9.89 (s, 1H); 13.86 (bs, 1H).

EXAMPLE 59 Preparation of Compound AS94

Using ethyl 4-(amino)benzoate and2-[5-(1,3-dipropyl-xanthin-8-yl)-1-methyl-pyrazol-3-yl)oxyacetic acid(Example 36), according to the method described in Example 36.

Yield: 48%; MP: 294° C.; 1H NMR (DMSO-d₆): δ 0.87 (m, 6H); 1.30 (m, 3H,J=8.00); 1.58 (m, 2H); 1.62 (m, 2H); 3.85 (m, 2H); 3.96 (m, 2H); 4.03(s, 3H); 4.24 (q, 2H, J=8.00); 4.80 (s, 2H); 6.44 (s, 1H); 7.77 (d, 2H,J=8.00); 7.92 (d, 2H, J=8.00); 10.46 (s, 1H); 13.92 (s, 1H).

EXAMPLE 60 Preparation of Compound AS95

Using 4-(amino)benzoic acid and2-[5-(1,3-dipropyl-xanthin-8-yl)-1-methyl-pyrazol-3-yl)oxyacetic acid(Example 36), according to the method described in Example 36.

Yield: 38%; MP: >300° C.; 1H NMR (DMSO-d₆): δ 0.88 (m, 6H); 1.56 (m,2H); 1.73 (m, 2H); 3.86 (m, 2H); 3.98 (m, 2H); 4.06 (s, 3H); 4.81 (s,2H); 6.49 (s, 1H); 7.74 (d, 2H, J=8.70); 7.80 (d, 2H, J=8.58); 10.44 (s,1H); 13.92 (s, 1H).

EXAMPLE 61 Preparation of Compound AS99

Using 3,4-dimethylaniline and2-[5-(1,3-dipropyl-xanthin-8-yl)-1-me-thyl-pyrazol-3-yl)oxyacetic acid(Example 36), according to the method described in Example 36.

Yield: 65%; MP: 264-265° C.; 1H NMR (DMSO-d₆): δ 0.88 (m, 6H); 1.57 (m,2H); 1.73 (m, 2H); 2.16 (m, 6H); 3.83 (m, 2H); 3.98 (m, 2H); 4.06 (s,3H); 4.73 (s, 2H); 6.51 (s, 1H); 7.31 (m, 1H); 7.34 (m, 2H); 9.93 (s,1H); 13.90 (s, 1H).

EXAMPLE 62 Preparation of Compound AS100

Using 3,4-dichloroaniline and2-[5-(1,3-dipropyl-xanthin-8-yl)-1-me-thyl-pyrazol-3-yl)oxyacetic acid(Example 36), according to the method described in Example 36.

Yield: 55%; MP: 258° C.; ¹H NMR (DMSO-d₆): δ 0.88 (m, 6H); 1.57 (m, 2H);1.72 (m, 2H); 3.84 (m, 2H); 4.00 (m, 2H); 4.06 (s, 3H); 4.78 (s, 2H);6.52 (s, 1H); 7.57 (s, 2H); 8.02 (s, 1H); 10.42 (s, 1H); 13.94 (s, 1H).

EXAMPLE 63 Preparation of Compound AS101

Using 3,4-dimethoxyaniline and2-[5-(1,3-dipropyl-xanthin-8-yl)-1-m-ethyl-pyrazol-3-yl)oxyacetic acid(Example 36), according to the method described in Example 36.

Yield: 60%; MP: 291-293° C.; ¹H NMR (DMSO-d₆): δ 0.88 (m, 6H); 1.59 (m,2H); 1.77 (m, 2H); 3.71 (m, 6H); 3.87 (m, 2H); 4.00 (m, 2H); 4.07 (s,3H); 4.73 (s, 2H); 6.51 (s, 1H); 6.89 (m, 1H); 7.14 (m, 1H); 7.33 (m,1H); 9.95 (s, 1H); 13.97 (s, 1H).

EXAMPLE 64 Preparation of Compound AS89

Using 4-aminopyridine and2-[5-(1,3-dipropyl-xanthin-8-yl)-1-methyl-pyrazol-3-yl)oxyacetic acid(Example 36), according to the method described in Example 36.

Yield: 35%; MP: 248-251° C.; ¹H NMR (DMSO-d₆): 60.9 (m, 6H); 1.55 (m,2H); 1.67 (m, 2H); 3.89 (m, 2H); 4.00 (m, 2H); 4.05 (s, 3H); 4.82 (s,2H); 6.44 (s, 1H); 7.64 (d, 2H, J=8.80); 7.93 (d, 2H, J=8.92); 10.43 (s,1H); 13.95 (bs, 1H).

EXAMPLE 65 Preparation of AS70

Using N-phenyl-piperazine and2-[5-(1,3-dipropyl-xanthin-8-yl)-1-me-thyl-pyrazol-3-yl)oxyacetic acid(Example 36), according to the method described in Example 36.

Yield: 38%; MP: 273-274° C.; ¹H NMR (DMSO-d₆): δ 0.87 (m, 6H); 1.69 (m,2H); 1.71 (m, 2H); 3.18 (m, 4H); 3.57 (m, 4H); 3.86 (m, 2H); 4.00 (m,2H); 4.05 (s, 2H); 6.46 (s, 1H); 6.81 (m, 1H); 6.96 (d, 2H, J=8.00);7.21 (t, 2H, J=8.00); 13.92 (s, 1H).

EXAMPLE 66 Preparation of AS72

Using N-(4-fluorophenyl)-piperazine and2-[5-(1,3-dipropyl-xanthin-8-yl)-1-methyl-pyrazol-3-yl)oxyacetic acid(Example 36), according to the method described in Example 36.

Yield: 40%; MP: 235-237° C.; ¹H NMR (DMSO-d₆): δ 0.87 (m, 6H); 1.57 (m,2H); 2H); 6.46 (s, 1H); 7.01 (m, 4H); 13.92 (s, 1H).

EXAMPLE 67 Preparation of AS87

Using N-methyl-piperazine and2-[5-(1,3-dipropyl-xanthin-8-yl)-1-me-thyl-pyrazol-3-yl)oxyacetic acid(Example 36), according to the method described in Example 36.

Yield: 56%; MP: 192-194° C.; ¹H NMR (DMSO-d₆): δ 0.87 (m, 6H); 1.06 (m,2H); 1.20 (m, 2H); 2.39 (m, 4H); 3.39 (m, 4H); 3.75 (m, 2H); 3.90 (s,3H); 4.12 (m, 2H); 4.04 (s, 3H); 4.85 (s, 2H); 6.92 (s, 1H); 13.92 (s,1H).

EXAMPLE 68 Preparation of AS90

Using N-benzyl-piperazine and2-[5-(1,3-dipropyl-xanthin-8-yl)-1-me-thyl-pyrazol-3-yl)oxyacetic acid(Example 36), according to the method described in Example 36.

Yield: 32%; MP: 236-237° C.; ¹H NMR (DMSO-d₆): δ 0.87 (m, 6H); 1.08 (m,2H); 1.12 (m, 2H); 2.39 (m, 4H); 3.39 (m, 4H); 3.50 (s, 2H); 3.86 (m,2H); 4.00 (m, 2H), 4.04 (s, 3H); 4.85 (s, 2H); 6.42 (s, 1H); 7.31 (m,5H); 13.92 (s, 1H).

EXAMPLE 69 Preparation of AS96

To a solution of ethyl (5-carboxy-1-methylpyrazol-3-yl)oxyacetic acid(0.5 mmol) and EDCl (0.5 mmol) in methanol (20 mL) was added a solutionof 1,3-diallyl-5,6-diaminouracil (0.5 mmol), dissolved in methanol (20mL). The mixture was stirred at room temperature for two hours, thesolvent was then removed in vacuo, water added, and the solid thatformed was collected by filtration and washed with additional coldwater. The intermediate amide was heated in 20 mL of 2.5 N NaOH at 70°C. for 30 minutes to afford the desired2-[5-(1,3-diallyl-xanthin-8-yl)-1-methyl-pyrazol-3-yl)oxyacetic acid.

Condensation of2-[5-(1,3-diallyl-xanthin-8-yl)-1-methyl-pyrazol-3-yl)oxyacetic acid(0.5 mmol) and N-phenyl-piperazine (1.3 mmol) in the presence of EDCl(1.12 mmol) and HOBt (1.14 mmol) in anhydrous dimethylformamide affordedthe desired product.

Yield: 27%; MP: 289-290° C.; ¹H NMR (DMSO-d₆): δ 3.17 (m, 4H); 3.57 (m,4H); 4.05 (s, 3H); 4.51 (m, 2H); 4.64 (m, 2H); 4.93 (s, 2H); 5.11 (m,4H); 5.89 (m, 2H); 6.46 (s, 1H); 6.81 (m, 1H); 6.96 (d, 2H, J=8.13);7.23 (t, 2H, J=8.00); 14.00 (s, 1H).

EXAMPLE 70 Preparation of AS105

Using N-(pyridin-2-yl)-piperazine and2-[5-(1,3-diallyl-xanthin-8-y-1)-1-methyl-pyrazol-3-yl)oxyacetic acid(Example 69), according to the method described in Example 69.

EXAMPLE 71 Preparation of AS106

Using N-(pyrimidin-2-yl)-piperazine and2-[5-(1,3-diallyl-xanthin-8-yl)-1-methyl-pyrazol-3-yl)oxyacetic acid(Example 69), according to the method described in Example 69.

EXAMPLE 72 Preparation of AS109

Using N-(4-sulfonamidophenyl)-piperazine and2-[5-(1,3-diallyl-xanthin-8-yl)-1-methyl-pyrazol-3-yl)oxyacetic acid(Example 69), according to the method described in Example 69.

EXAMPLE 73 Preparation of ethyl(5-(methoxycarbonyl)-isoxazol-3-yl)oxyacetate

To a solution of methyl 3-hydroxy-isoxazole-5-carboxylate (7.14 mmol) inacetone (30 mL), was added potassium carbonate (1.2 g, 8.6 mmol) andethyl bromoacetate (8.6 mmol). The reaction mixture was heated at refluxfor 2 h, monitoring by TLC. At completion, acetone was removed in vacuoand the residue partitioned between water and ethyl acetate (50 mL). Theorganic layer was dried (MgSO₄), filtered, and evaporated to afford thedesired intermediate.

Yield: 81%; MP: 66-67° C.; ¹H NMR (CDCl₃): δ 1.30 (t, 3H, J=7.22); 3.96(s, 3H); 4.27 (q, 2H, J=7.21); 4.87 (s, 2H); 6.65 (s, 1H).

EXAMPLE 74 Preparation of (5-carboxyisoxazol-3-yl)oxyacetic Acid

A solution of ethyl (5-(methoxycarbonyl)isoxazol-3-yl)oxyacetate (4mmol, Example 73) in methanol (60 mL) and 5% aqueous NaOH is heated atreflux for 1 hour. At the end of this time, the methanol is removed, theresidue diluted with additional water, and acidified to pH=4 withhydrochloric acid. The resulting precipitate is collected by filtration,washed with cold water, and dried.

Yield: 90%; MP: >300° C.; ¹H NMR (DMSO-d₆): 0 4.71 (s, 2H); 6.22 (s,1H); 11.30 (bs, 1H); 14.75 (bs, 1H).

EXAMPLE 75 Preparation of ethyl (5-carboxyisoxazol-3-yl)oxyacetate

(5-Carboxyisoxazol-3-yl)oxyacetic acid (4.0 mmol, Example 74) isdissolved in ethanol (50 mL), to which is added a catalytic amount ofp-toluenesulfonic acid (100 mg). After stirring overnight at roomtemperature, the ethanol was removed and the residue was recrystallizedfrom ethanol/water.

Yield: 70%; MP: 145-150° C.; ¹H NMR (CDCl₃): [1.40 (t, 3H, J=7.18); 4.20(q, 2H, J=7.21); 4.90 (s, 2H); 6.75 (s, 1H); 11.35 (bs, 1H).

EXAMPLE 76 Preparation of AS74

To a solution of ethyl (5-carboxyisoxazol-3-yl)oxyacetic acid (0.5 mmol)and EDCl (0.5 mmol) in methanol (20 mL) was added a solution of1,3-dipropyl-5,6-diaminouracil (0.5 mmol), dissolved in methanol (20mL). The mixture was stirred at room temperature for two hours, thesolvent was then removed in vacuo, water added, and the solid thatformed was collected by filtration and washed with additional coldwater. The intermediate amide was heated in 20 mL of 2.5 N NaOH at 70°C. for 30 minutes to afford the desired2-[5-(1,3-dipropyl-xanthin-8-yl)-isoxazo-1-3-yl)oxyacetic acid.

Condensation of2-[5-(1,3-dipropyl-xanthin-8-yl)-isoxazol-3-yl)oxya-cetic acid (0.5mmol) and 3,4-methylenedioxyaniline (1.3 mmol) in the presence of EDCl(1.12 mmol) and HOBt (1.14 mmol) in anhydrous dimethylformamide affordedthe desired product.

EXAMPLE 77 Preparation of AS76

Using 3,4-dimethoxyaniline and2-[5-(1,3-dipropyl-xanthin-8-yl)-iso-xazol-3-yl)oxyacetic acid (Example76), according to the method described in Example 76.

Yield: 36%; MP: 253-255° C.; ¹H NMR (DMSO-d₆): δ 0.88 (m, 6H); 1.55 (m,2H); 1.70 (m, 2H); 3.72 (s, 6H); 3.85 (m, 2H); 3.97 (m, 2H); 4.90 (s,2H); 6.90 (m, 2H); 7.12 (m, 1H); 7.30 (s, 1H); 10.10 (bs, 1H); 14.60(bs, 1H).

EXAMPLE 78 Preparation of AS73

Using 4-fluoroaniline and2-[5-(1,3-dipropyl-xanthin-8-yl)-isoxazol-3-yl)oxyacetic acid (Example76), according to the method described in Example 76.

Yield: 28%; MP: 287° C.; ¹H NMR (DMSO-d₆): δ 0.88 (m, 6H); 1.55 (m, 2H);1.70 (m, 2H); 3.85 (m, 2H); 3.97 (m, 2H); 4.93 (s, 2H); 6.90 (s, 1H);7.18 (m, 2H); 7.62 (m, 2H); 10.29 (bs, 1H); 14.60 (bs, 1H).

EXAMPLE 79 Preparation of AS75

Using 4-methoxyaniline and2-[5-(1,3-dipropyl-xanthin-8-yl)-isoxazo-1-3-yl)oxyacetic acid (Example76), according to the method described in Example 76.

Yield: 38%; MP: 285-287° C.; ¹H NMR (DMSO-d₆): δ 0.88 (m, 6H); 1.59 (m,2H); 1.68 (m, 2H); 3.71 (s, 3H); 3.85 (m, 2H); 3.97 (m, 2H); 4.90 (s,2H); 6.91 (m, 3H); 7.50 (m, 2H); 10.09 (s, 1H); 14.56 (bs, 1H).

EXAMPLE 80 Preparation of 2-bromo-N-(4-iodophenyl)acetamide

To a solution of 4-iodoaniline (14.5 mmol) in anhydrous dichloromethaneat 0° C. was added a-bromo-acetylbromide (1.4 mL) and triethylamine (15mmol). The mixture was warmed to room temperature, stirred for 1 h, thesolvent removed, and residue dissolved in 5% hydrochloric acid. Theaqueous solution was extracted with ethyl acetate, the organic layerwashed with brine, dried (Na2SO4), filtered, and evaporated. The solidresidue was purified by recrystallization form ethyl acetate to affordthe desired intermediate.

Yield: 60%; MP: 185° C.; ¹H NMR (CDCl₃): δ 4.93 (s, 2H); 8.24 (d, 2H,J=8.00); 8.58 (d, 2H, J=8.00); 9.02 (bs,1H).

EXAMPLE 81 Preparation of1,3-dipropyl-8-(6-hydroxy-pyridazin-3-yl)-xanthine

To a solution of 1,3-dipropyl-5,6-diaminouracil (2.2 mmol) in methanolwas added an equimolar amount of 6-hydroxy-pyridazine-3-carboxylic acid,followed by a slight excess of DCl((N-(3-(dimethylamino)propyl)-N′ethylcarbodiimide hydrochloride). Themixture was stirred at room temperature for 4-5 hours until complete byTLC. Water was then added and the precipitate removed by filtration. Thesolid was dissolved in 10% aqueous NaOH (20 mL), then heated at 70° C.for 30 minutes. After cooling to room temperature, the reaction mixturewas acidified to pH=5 with 10% hydrochloric acid and the precipitatedproduct collected by filtration.

Yield: 30%; MP: 216° C.; ¹H NMR (DMSO-d₆): δ 0.87 (m, 6H); 1.65 (m, 4H);3.5 (bs, 1H), 3.84 (m, 2H); 3.97 (m, 2H); 6.99 (d, 1H); 8.04 (d, 1H);13.32 (bs, 1H).

EXAMPLE 82 Preparation of AS85

To a solution of 1,3-dipropyl-8-(6-hydroxy-pyridazin-3-yl)-xanthine(0.20 mmol, Example 81) in anhydrous dimethylformamide (10 mL) was addedan equimolar amount of triethylamine. The reaction mixture was stirredat room temperature for 10 minutes, followed by the addition of2-bromo-N-(4-iodophenyl)acetamide (0.20 mmol, Example 80). Afterstirring at room temperature overnight, the solvent was distilled off,the residue was taken up in cold water, and the precipitated productcollected by filtration. The product was further purified by columnchromatography on silica gel, eluting with a mixture of dichloromethaneand methanol.

Yield: 28%; MP: 310° C.; ¹H NMR (DMSO-d₆): δ 0.86 (m, 6H); 1.55 (m, 2H);1.76 (m, 2H); 3.80 (m, 2H); 4.03 (m, 2H); 5.58 (s, 2H); 7.04 (d, 1H,J=9.92); 7.37 (d, 2H, J=8.64); 7.65 (d, 2H, J=8.55); 8.09 (d, 1H,J=10.01); 10.45 (s,1H); 13.30 (bs,1H).

EXAMPLE 83 Preparation of AS103

To a solution of 1,3-dipropyl-5,6-diaminouracil (2.2 mmol) in methanolwas added an equimolar amount of 2-hydroxy-pyridine-5-carboxylic acid,followed by a slight excess of DCl((N-(3-(dimethylamino)propyl)-N′-ethylcarbodiimide hydrochloride). Themixture was stirred at room temperature for 4-5 hours until complete byTLC. Water was then added and the precipitate removed by filtration. Thesolid was dissolved in 10% aqueous NaOH (20 mL), then heated at 70° C.for 30 minutes. After cooling to room temperature, the reaction mixturewas acidified to pH=5 with 10% hydrochloric acid and the precipitatedproduct collected by filtration.

Yield: 25%; MP: >300° C.; ¹H NMR (DMSO-d₆): δ 0.88 (m, 6H); 1.60 (m,4H);3.84 (bs,1H); 3.84 (m, 2H); 3.97 (m, 2H); 6.47 (d, 1H); 8.08 (m,1H);8.20 (m, 1H); 13.30 (bs, 1H).

EXAMPLE 84 Preparation of AS81

To a solution of 1,3-dipropyl-8-(2-hydroxy-pyridin-5-yl)-xanthine (0.20mmol, Example 81) in anhydrous dimethylformamide (10 mL) was added anequimolar amount of triethylamine. The reaction mixture was stirred atroom temperature for 10 minutes, followed by the addition of2-bromo-N-(4-iodophenyl)acetamide (0.20 mmol, Example 80). Afterstirring at room temperature overnight, the solvent was distilled off,the residue was taken up in cold water, and the precipitated productcollected by filtration. The product was further purified by columnchromatography on silica gel, eluting with a mixture of dichloromethaneand methanol.

Yield: 25%; MP: 293° C.; ¹H NMR (DMSO-d₆): δ 0.86 (m, 6H); 1.55 (m, 2H);1.76 (m, 2H); 3.80 (m, 2H); 3.89 (m, 2H); 5.21 (s, 2H); 6.37 (d, 1H,J=9.46); 7.45 )d,

EXAMPLE 85 Preparation of Compound AS68a

To a solution of ethyl (5-carboxy-1-methylpyrazol-3-yl)oxyacetic acid(0.5 mmol) and EDCl (0.5 mmol) in methanol (20 mL) was added a solutionof 1,3-diallyl-5,6-diaminouracil (0.5 mmol), dissolved in methanol (20mL). The mixture was stirred at room temperature for two hours, thesolvent was then removed in vacuo, water added, and the solid thatformed was collected by filtration and washed with additional coldwater. The intermediate amide was heated in 20 mL of 2.5 N NaOH at 70°C. for 30 minutes to afford the desired2-[5-(1,3-dipropyl-xanthin-8-yl)-1-methyl-pyrazol-3-yl)oxyacetic acid.

Condensation of2-[5-(1,3-dipropyl-xanthin-8-yl)-1-methyl-pyrazol-3-yl)oxyacetic acid(0.5 mmol) and 3,4-methylenedioxyaniline (1.3 mmol) in the presence ofEDCl (1.12 mmol) and HOBt (1.14 mmol) in anhydrous dimethylformamideafforded the desired product.

MP: 288-289° C.; 1H-NMR (DMSO-d₆): δ 2.50 (s, 3H), 4.51 (d, 2H), 4.62(d, 2H), 4.72 (s, 2H), 5.07 (d, 1H), 5.10 (d, 1H), 5.15 (s, 1H), 5.18(d, 1H), 5.90 (m, 2H), 5.98 (s, 2H), 6.51 (s, 1H), 6.87 (d, 1H,J=8.44Hz), 7.01 (d, 1H), 7.32 (s, 1H), 10.01 (s, 1H); 14.01 (bs, 1H).

Preparation of Radioligand Compounds

The compounds can be labeled with any suitable radiolabel. Examples ofsuitable radiolabels include tritium (³H) and carbon radioisotopes (e.g.¹⁴C), but any substantially non-toxic radiolabel commonly used inpharmacokinetic studies can be used. Means for incorporating radiolabelsonto organic compounds are well known to those of skill in the art.

When the compounds are synthesized from a starting1,3-dialkyl-5,6-diaminouracil, incorporation of a radiolabel is fairlystraightforward. For example, the diaminouracil can be obtainedcontaining a suitable radiolabel. As an alternate, the diaminouracil canbe obtained with one or more sites of unsaturation in an attachedsubstituent (e.g. iso-propylene in place of isopropyl). The unsaturateddouble bond can then be reacted with tritium in the presence a suitablecatalyst, for example, palladium on charcoal or other knownhydrogenation catalysts. Using the radiolabelled diaminouracil andfollowing the methods of synthesis herein described will result in thecorresponding radiolabelled compound.

It has been established by the inventors, as well as known by thoseskilled in the art, that ³H and ¹⁴C labeled compounds have bindingaffinity to the adenosine A₁, A_(2A), A_(2B), and A₃ A_(2B), and A₃receptor subtypes comparable to that of corresponding non-labeled forms.

In another embodiment, the radiolabel can be incorporated into themolecule while the ring system is being put together. As discussed abovewith respect to the synthesis of the compounds of Formula II, varioustricyclic compounds of Formula VI are hydrolyzed with HCl to givetriazoles of Formula VII, which are cyclized to with cyanamide at refluxin the presence of para-toluenesulfonic acid, as shown in Scheme I. Itis relatively straightforward to incorporate a ¹⁴C label at this step inthe synthesis using ¹⁴C labeled cyanamide.

EXAMPLE 86 Preparation of Radioligand of Compound AS16

A solution of 1,3-diallyl-5,6-diaminouracil (0.7 g, 0.003 mol),1-methyl-3-(benzyloxycarbonylamino)-pyrazole-5-carboxylic acid (0.8 g,0.003 mol), and EDCl (0.6 g, 0.003 mol) in 50 mL of CH₃OH is stirred atroom temperature for two hours. Excess CH₃OH is evaporated in vacuo togive a yellow solid that is collected by filtration and washed with H₂Oto give the amide intermediate.

A mixture of the amide intermediate and 30 mL of 2.5 N NaOH is warmed to70-80° C. for three hours. The clear aqueous solution is cooled andacidified to pH 5 with concentrated HCl. The white precipitate thatforms is collected by filtration and washed with H₂O to afford thedesired 1,3-diallyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine, which isrecrystallized from CH₃OH. A solution of 4-(benzyloxy)phenylaceti-c acid(0.196 mmol) in 3 mL of thionyl chloride is stirred at 70° C. for fourhours, then excess thionyl chloride removed in a nitrogen stream.

A solution of 1,3-diallyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine(0.151 mmol, Example 1) and 0.04 mL of anhydrous triethyl amine in 10 mLof CH₂Cl₂: CH₃OH (1:1) is added and the mixture is stirred at roomtemperature for 24 hours, monitoring by TLC. At completion, the solventis evaporated, the residue is dissolved in ethyl acetate, and thesolution washed with saturated aqueous NaHCO₃ and brine. The organiclayer is dried (Na₂SO₄), filtered, and evaporated in vacuo. The desiredintermediate is purified by column chromatography on silica gel.

To a suspension of 10% Pd/C (5 mg) in CH₃CH₂OH (10 mL) is added asolution of1,3-diallyl-8-(3-(2-(4-(benzyloxy)phenyl)acetylamino-)-1-methylpyrazol-5-yl)xanthinein CH₃CH₂OH (3 mL). The mixture is evacuated and charged with tritiumgas to 50 psi, then shaken at room temperature for 16 hours. The mixtureis evacuated, the solution filtered to remove catalyst, and the solutionevaporated in vacuo. The residue is purified by column chromatography toprovide the desired tritiated analogue, identical chromatographically toExample 7.

EXAMPLE 87 Preparation of Radioligand of Compound AS68

To a solution of ethyl (5-[¹⁴C]-carboxy-1-methylpyrazol-3-yl)o-xyaceticacid (0.5 mmol) and EDCl (0.5 mmol) in methanol (20 mL) is added asolution of 1,3-dipropyl-5,6-diaminouracil (0.5 mmol), dissolved inmethanol (20 mL). The mixture is stirred at room temperature for twohours, the solvent is then removed in vacuo, water is added, and thesolid that forms is collected by filtration and washed with additionalcold water. The intermediate amide is heated in 20 mL of 2.5 N NaOH at70° C. for 30 minutes to afford the desired2-[5-(1,3-dipropyl-8-[¹⁴C]-xanthin-8-yl)-1-methyl-pyrazol-3-yl)oxyacetic

Condensation of2-[5-(1,3-dipropyl-[¹⁴C]-8-[xanthin-8-yl)-1-me-thyl-pyrazol-3-yl)oxyaceticacid (0.5 mmol) and 3,4-methylenedioxyaniline (1.3 mmol) in the presenceof EDCl (1.12 mmol) and HOBt (1.14 mmol) in anhydrous dimethylformamideaffords the desired [¹⁴C]-labeled product, identical chromatographicallywith Example 39.

Preparation of Fluorescently Labeled Compounds

As with the radiolabelled compounds, the synthesis of fluorescentlylabeled compounds is relatively straightforward. Chemical bonding offluorescent labels, with or without a linking or tethering group, tooligomeric compounds, is well known in the art (see for example: Hill,J. J. and Royer, C. A., Methods Enzymol., 1997, 278, 390-416; and Amannet al., Microbiol. Rev., 1997, 20, 191-200). Typically, the fluorescentlabel is attached via a covalent bond using a tethering moiety.Additional techniques and uses of fluorescently labeled compounds aredisclosed in U.S. Pat. No. 6,127,124 to Leeds et al., incorporatedherein by reference.

The compounds of the present invention can be used in vitro forscientific studies requiring highly selective A_(2B) radioligands. Forexample, the present inventive 8-heteroaryl xanthine derivatives may beused to probe adenosine receptors in order to isolate or characterizethe receptors.

Additionally, the compounds of the present invention can be used in vivofor treating diseases induced by activation of the adenosine A_(2B)receptor and inflammatory diseases involving degranulation of mast cellsincluding asthma, chronic obstructive pulmonary disease, rheumatoidarthritis, allergic rhinitis, allergic dermatitis and bee sting;impaired sensitivity to insulin including Type 2 diabetes or non-insulindependent diabetes, pre-diabetic state, and impaired glucose tolerance;diseases in which angiogenesis is a key component of pathogenesisincluding solid tumors and angiogenic retinopathies; and apnea ofpreterm infants.

Furthermore, following the teachings of Belardinelli, the compounds ofthe present invention may be used for inhibiting cell proliferation incells that express the A_(2B) adenosine receptor including human retinalendothelial cells (HREC). Such uses include treatment for chronic andacute inflammatory diseases involving degranulation of mast cellsincluding asthma, chronic obstructive pulmonary disease, rheumatoidarthritis, allergic rhinitis, allergic dermatitis and bee sting;impaired sensitivity to insulin including Type 2 diabetes or non-insulindependent diabetes, pre-diabetic state, and impaired glucose tolerance;diseases in which angiogenesis is a key component of pathogenesisincluding solid tumors and angiogenic retinopathies; and apnea ofpreterm infants; myocardial reperfusion injury, inflammatory boweldisease, and autoimmune diseases such as rheumatoid arthritis, multiplesclerosis (MS) and lupus erythematosis.

Similarly, the compounds can be used in a method for the treatment ofdiseases involving microvascular abnormalities of the retina that aremediated by adenosine A_(2B) receptors. Such diseases include, but arenot limited to, retinopathy, prematurity, macular degeneration, anddiabetic retinopathy.

The compounds of the present invention can be formulated aspharmaceutical compositions and administered to a mammalian host, suchas a human patient in a variety of forms adapted to the chosen route ofadministration, i.e., orally or parenterally, by intravenous,intramuscular, topical, inhalation or subcutaneous routes. Thus, thepresent compounds may be systemically administered, e.g., orally, incombination with a pharmaceutically acceptable vehicle such as an inertdiluent or an assimilable edible carrier. They may be enclosed in hardor soft shell gelatin capsules, may be compressed into tablets or may beincorporated directly with the food of the patient's diet.

For oral therapeutic administration, the active compound may be combinedwith one or more excipients and used in the form of ingestible tablets,buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers,and the like. Such compositions and preparations should contain at least0.1% of active compound. The percentage of the compositions andpreparations may, of course, be varied and may conveniently be betweenabout 2 to about 60% of the weight of a given unit dosage form. Theamount of active compound in such therapeutically useful compositions issuch that an effective dosage level will be obtained.

The tablets, troches, pills, capsules, and the like may also contain thefollowing: binders such as gum tragacanth, acacia, corn starch orgelatin; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, fructose, lactose or aspartame or a flavoring agent such aspeppermint, oil of wintergreen or cherry flavoring may be added. Whenthe unit dosage form is a capsule, it may contain, in addition tomaterials of the above type, a liquid carrier, such as a vegetable oilor a polyethylene glycol.

Various other materials may be present as coatings or to otherwisemodify the physical form of the solid unit dosage form. For instance,tablets, pills or capsules may be coated with gelatin, wax, shellac orsugar and the like. A syrup or elixir may contain the active compound,sucrose or fructose as a sweetening agent, methyl and propylparabens aspreservatives, a dye and flavoring such as cherry or orange flavor.

It is desirable that any material used in preparing any unit dosage formshould be pharmaceutically acceptable and substantially non-toxic in theamounts employed. In addition, the active compound may be incorporatedinto sustained release preparations and devices.

The active compound may also be administered intravenously orintraperitoneally by infusion or injection. Solutions of the activecompound or its salts can be prepared in water, optionally mixed with anontoxic surfactant. Dispersions can also be prepared in glycerol,liquid polyethylene glycols, triacetin, and mixtures thereof and inoils. Under ordinary conditions of storage and use, these preparationscontain a preservative to prevent the growth of microorganisms.

The pharmaceutical dosage forms suitable for injection or infusion caninclude sterile aqueous solutions or dispersions or sterile powderscomprising the active compound of the present invention that is furtheradapted for the extemporaneous preparation of sterile injectable orinfusible solutions or dispersions, optionally encapsulated inliposomes. In all cases, the ultimate dosage form is preferably sterile,fluid and stable under the conditions of manufacture and storage. Theliquid carrier or vehicle can be a solvent or liquid dispersion mediumsuch as, water, ethanol, a polyol (for example, glycerol, propyleneglycol, liquid polyethylene glycols, and the like), vegetable oils,nontoxic glyceryl esters, and suitable mixtures thereof. The properfluidity can be maintained, for example, by the formation of liposomes,by the maintenance of the required particle size in the case ofdispersions or by the use of surfactants.

The prevention of the action of microorganisms can be brought about byvarious antibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In manycases, it will be preferable to include isotonic agents, for example,sugars, buffers or sodium chloride. Prolonged absorption of theinjectable compositions can be brought about by the use in thecompositions of agents delaying absorption, for example, aluminummonostearate and celatin.

Sterile injectable solutions are prepared by incorporating the activecompound in the required amount of the appropriate solvent with variousother ingredients enumerated above, as required, followed by filtersterilization. In the case of sterile powders for the preparation ofsterile injectable solutions, the preferred methods of preparation arevacuum drying and freeze drying techniques, which yield a powder of theactive compound plus any additional desired ingredient.

For topical administration, the present compounds may be applied in pureform, i.e., when they are liquids. However, it will generally bedesirable to administer them to the skin as compositions orformulations, in combination with a dermatologically acceptable carrier,which may be a solid or a liquid.

Useful solid carriers include finely divided solids such as talc, clay,microcrystalline cellulose, silica, alumina and the like. Useful liquidcarriers include water, alcohols or glycols or water-alcohol/glycolblends, in which the present compounds can be dissolved or dispersed ateffective levels, optionally with the aid of non-toxic surfactants.Adjuvants such as fragrances and additional antimicrobial agents can beadded to optimize the properties for a given use. The resultant liquidcompositions can be applied from absorbent pads, used to impregnatebandages and other dressings or sprayed onto the affected area usingpump-type or aerosol sprayers.

Thickeners such as synthetic polymers, fatty acids, fatty acid salts andesters, fatty alcohols, modified celluloses or modified mineralmaterials can also be employed with liquid carriers to form spreadablepastes, gels, ointments, soaps, and the like, for application directlyto the skin of the user.

Examples of useful dermatological compositions which, can be used todeliver the compounds of present invention to the skin are known in theart, for example, as described in U.S. Pat. Nos. 4,608,392, 4,992,478,4,559,157 and 4,820,508.

Useful dosages of the compounds of the present invention can bedetermined by comparing their in vitro activity, and in vivo activity inanimal models. Methods for the: extrapolation of effective dosages inmice, and other animals, to humans are known to the art; for example,see U.S. Pat. No. 4,938,949.

Generally, the concentration of the compound(s) of the present inventionin a liquid composition, such as a lotion, will be from about 0.01-25wt-%, preferably from about 0.1-10 wt-%. The concentration in asemi-solid or solid composition such as a gel or a powder will be about0. 1-5 wt-%, preferably about 0.5-2.5 wt %.

The amount of the compound or an active salt or derivative required foruse in treatment will vary not only with the particular salt selectedbut also with the route of administration, the nature of the conditionbeing treated and the age and condition of the patient and will beultimately at the discretion of the administering physician orclinician. In general, a suitable dose will be in the range of fromabout 0.001 mg/kg/day to about 20 mg/kg/day. For example, a dosage maybe from 0.002 mg/kg/day to about 10 mg/kg of body weight per day,preferably in the range of 0.0l mg/kg/day to 1 mg/kg/day, and mostpreferably in the range of 0.1 mg/kg/day to 5 mg/kg/day.

The compound is conveniently administered in unit dosage form; forexample, containing 5 to 1000 μg, conveniently 10 to 750 μg, mostconveniently, 50 to 500 μg of active ingredient per unit dosage form.

The compounds of the invention can be administered by inhalation from aninhaler, insufflator, atomizer or pressurized pack or other means ofdelivering an aerosol spray. Pressurized packs may use a suitablepropellant such as carbon dioxide or other suitable gas. In the case ofa pressurized aerosol, the dosage unit may be determined by providing avalue to deliver a metered amount. The inhalers, insufflators, andatomizers are fully described in pharmaceutical reference books such asRemington's Pharmaceutical Sciences 18th edition (1990) Mack PublishingCo., Easton, Pa.

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of discrete loosely spacedadministrations; such as multiple inhalations from an insufflator or byapplication of a plurality of drops into the eye. Dosages above or belowthe range cited above are within the scope of the present invention andmay be administered to the individual patient if desired and necessary.

When used in the treatment of treatment for ischemic injury to retinalvessels the compounds of the present invention are preferably formulatedin eyedrops suitable for topical application.

Biological Assays

All synthesized compounds have been tested for their affinity to humanA1, A_(2A), A_(2B) and A₃ adenosine receptors expressed in ChineseHamster Ovary cells (CHO) (A₁, A_(2A) and A₃) and HEK 293 cells (A_(2B)) using cell binding assay techniques known in the art.

The cells were grown adherently and maintained in Dulbecco's modifiedEagle's medium with nutrient mixture F12 without nucleosides at 37° C.in 5% CO_(2/95)% air. The cells were washed with phosphate-bufferedsaline and scraped off flasks in ice cold hypotonic buffer (5 nM TrisHCl, 2 mM EDTA, pH 7.4). The cell suspension was homogenized with aPolytron and the homogenate was centrifuged for 30 minutes at 48,000 g.The resultant membrane pellet was re-suspended in 50 mM Tris HCl bufferat pH 7.4 for A₁ adenosine receptors; in 50 mM Tris HCl 10 mM MgCl, atpH 7.4 for A_(2A) adenosine receptors; in 50 mM Tris HCl, 10 mM MgCl₂, 1mM EDTA, at pH 7.4 for A₃ adenosine receptors and were utilized forbinding assays.

HEK 293 cells transfected with the human recombinant A_(2B) adenosinereceptor were obtained from Receptor Biology, Inc. (Beltsville, Md.USA).

Binding of [³H]-DPCPX to CHO cells transfected with the humanrecombinant A₁ adenosine receptor was performed according to the methodpreviously described by Klotz et al. 1985. Displacement experiments wereperformed for 120 minutes at 25° C. in 200 μl of buffer containing 1 nM³H]-DPCPX 20 μl of diluted membranes (50 μg of protein/assay) and atleast 6 to 8 different concentrations of examined compounds.Non-specific binding was determined in the presence of 10 μM of CHA andthis is always less than 10% of the total binding.

Binding of [³H]ZM-241385 to CHO cells transfected with the humanrecombinant A_(2A) adenosine receptors (50 μg of protein/assay) wasperformed according to Varani et al., 2000. In competition studies, atleast 6-8 different concentrations of compounds were used andnon-specific binding was determined in the presence of 1 μM ZM-241385with an incubation time of 60 minutes at 25° C.

Binding of 1 [³H]-DPCPX to HEK 293 cells transfected with the humanrecombinant A_(2B) adenosine receptors was performed according to themethod described by Varani et al., 2000. In particular, assays werecarried out for 60 minutes at 25° C. in 100 μl of 50 nM Tris HCl buffer,10 nM MgCl₂, 1 mM EDTA, 0.1 mM benzamidine pH 7.4, 2 IU/ml adenosinedeaminase containing 40 nM [³H]-DPCPX, diluted membranes (20 μg ofprotein/assay) and at least 6-8 different concentration of testedcompounds. Non-specific binding was determined in the presence of 100 μMof NECA and was always less than 30% of the total binding.

Binding of [³H]-MRE3008-F20 to CHO cells transfected with the humanrecombinant A₃ adenosine receptors was performed according to Varani etal., 2000. Competition experiments were carried out in duplicate in afinal volume of 250 μl in test tubes containing 1 nM [³H]-MRE3008-F20,50 mM Tris HCl buffer, 10 nM MgCl₂, pH 7.4 and 100 μl of dilutedmembranes (50μg of protein/assay) and at least 6-8 differentconcentrations of examined ligands for 120 minutes at 4° C. Non-specificbinding was defined as binding in the presence of 1 μM [³H]-MRE3008-F20and was about 25% of total binding.

Bound and free radioactivity portions were separated by filtering theassay mixture through Whatman GF/B glass-fiber filters using aMicro-Mate 196 cell harvester (Packard Instrument Company). The filterbound radioactivity was counted on Top Count (efficiency 57%) withMicro-Scint 20. The protein concentration was determined according to aBio-Rad method (Bradford, 1976) with bovine albumin as referencestandard.

Measurement of cyclic AMP (CAMP) levels in CHO cells transfected withhuman A_(2B) adenosine receptors was performed in the following manner.CHO cells transfected with human A₂B adenosine receptors were washedwith phosphate-buffered saline, diluted tripsine and centrifuged for 10minutes at 200 g. The pellet containing the CHO cells (1.times.10⁶cells/assay) was suspended in 0.5 ml of incubation mixture (mM): 15 mMNaCl, 0.27 mM KC1, 0.037 mM NaH₂PO₄, 0.1 mM MgSO₄, 0.1 CaCl₂, 0.01 mMHepes, 1 mM MgCl, 0.5 mM glucose, pH 7.4 at 37° C., 2 IU/ml adenosinedeaminase and 4-(3-butoxy-4methoxybenzyl)-2-imidazolidinone (Ro 20-1724)as phosphodiesterase inhibitor and preincubated for 10 minutes in ashaking bath at 37° C.

The potencies of antagonists studied were determined by antagonism ofNECA (100 nM)-induced stimulation of cAMP levels. The reaction wasterminated by the addition of cold 6% thrichloroacetic acid (TCA). TheTCA suspension was centrifuged at 2000 g for 10 minutes at 4° C. and thesupernatant was extracted four times with water saturated diethyl ether.The final aqueous, solution was tested for cAMP levels by a competitionprotein binding assay. Samples of cAMP standard (0-10 pmoles) were addedto each test tube containing the incubation buffer (trizma base 0.1 M,aminophylline 8.0 mM, 2-mercaptoethanol 6.0 mM, pH 7.4) and [H³]-cAMP ina total volume of 0.5 ml. The binding protein previously prepared frombeef adrenals, was added to the samples previously incubated at 4° C.for 150 minutes, and after the addition of charcoal were centrifuged at2000 g for 10 minutes. The clear supernatant was counted in a Beckmanscintillation counter.

Data Analysis

The filter bound radioactivity was counted on a Top Count brandMicroplate Scintillation Counter (efficiency 57%) with Micro-Scint 20.The protein concentration was determined according to a Bio-Rad method(Bradford. 1976) with bovine albumin as a standard reference. Inhibitorybinding constant K_(i) values were calculated from those of IC₅0according to the Cheng and Prusoff equation (Cheng and Prusoff, 1973):K _(i) =IC ₅0/(1+[C*]/K _(D)*),where [C*] is the concentration of the radioligand and K_(D)* is itsdissociation constant. The weighted non-linear least-squares curvefitting program LIGAND (Munson & Rodboard, 1980) was used for computeranalysis of saturation and inhibition experiments. All data (K_(i) andIC₅0) are expressed as geometric means with 95% confidence intervals.Results and Discussion

Binding results, expressed as K; for the synthesized compounds AS3 toAS69 are reported in Table 1. A binding of greater than 10,000 nM (10μM) is indicated when no appreciable binding was measured. As is seen inTable 1, the compounds of the present invention present a wide range ofbinding affinities hence making selection of antagonism for variousadenosine receptor subtypes possible. For example, a compound such asAS68 is a highly potent A_(2B) antagonist and retains significant Alantagonism. Compound such as AS28 provide less A_(2B) affinity but aretotally selective with no appreciable binding to the other adenosinereceptor subtypes.

The Compound AS68 has the highest measured affinity for the human A_(2B)receptors (K_(i)=5.5 nM), binding to adenosine A₁ receptors (K_(i)=200nM) but appears to show little or no affinity to human A_(2A) and A₃adenosine receptors subtypes. The compounds AS29, AS39, AS57, AS64 andAS65 have good affinity for the human A_(2B) receptors with an affinityvalue in the nanomolar range (K_(i)=9-20 nM). Other compounds such asAS11, AS27, AS28, AS35 and AS54 showed a K_(i) value in the nanomolarrange (K_(i)=28-39 nM) for A_(2B) receptors. Compounds AS13, AS15, AS16and AS17 show affinity in nanomolar range (K_(i)=56-103 nM) to the humanA_(2B) receptor, with no appreciable affinity for the other adenosinereceptor subtypes. TABLE 1 Binding Affinites to Adenosine Receptors Ki(nM) [3H]MRE3008F20 binding to human A3 13HIDPCPX binding to[3H]ZM241385 binding to [3H]DPCPX binding to receptors Compound human A1receptors human A2A receptors human AM receptors expressed in CHO Numberexpressed in CHO cells expensed in CHO cells expressed in HEK293 cellscells AS3 201(172-236) >1000  235(209-264) >1000 AS11 900(811-996) >100035(27-45) >1000 AS12 >1000 >1000 >1000 >1000 AS13 >1000 >1000 96(80-114) >1000 AS14 >1000 >1000 >1000 >1000 AS15 >1000 >100078(63-96) >1000 AS16 >1000 >1000 56(42-77) >1000 AS17 >1000 >1000103(79-136) >1000 AS18 >1000 >1000 >1000 >1000AS19 >1000 >1000 >1000 >1000 AS21 >1000 >1000 >1000 >1000 AS22200(166-240) >1000 88(84-92) >1000 AS23 850(762-946) >1000100(83-120) >1000 AS24  4481(3650-5501) >1000  160(142-179) >1000 AS25 3227(2799-3720) >1000 50(41-60) >1000 AS26 >1000 >1000 1628(1374-1930) >1000 AS27 520(484-558) >1000 28(23-33) >1000AS28 >1000 >1000 38(33-43) >1000 AS29 56(47-67)  >1000 13(11-16) >1000AS30 100(83-120)  >1000  90(73-110) >1000 AS31 163(137-193) >1000 111(100-124) >1000 AS32 746(659-843) >1000  190(172-209) >1000 AS43 1898(1723-2091) >1000  130(113-150) >1000 AS44 >1000 >1000 >1000 >1000AS56  1793(1460-2201) 2433(1675-3533) 100(83-120) >1000 AS57566(516-621) 1249(856-1822)  18(12-27) >1000 AS58 >1000 1755(1343-2292) 342(274-426) >1000 AS8 >1000 >1000 >1000 >1000AS9 >1000 >1000 >1000 >1000 AS10 548(464-648) >1000 2065(1866-2284) >1000 AS38 >1000 >1000  175(134-229) >1000AS40 >1000 >1000  569(506-640) >1000 AS7 122(84-177)  >1000 342(274-426) >1000 AS36 >1000 >1000 >1000 >1000AS33 >1000 >1000 >1000 >1000 AS59 >1000 >1000  1012(819-1250) >1000 AS6465(48-86)  >1000 12(7-21) >1000 AS65 150(132-170) >1000 20(16-25) >1000AS68 200(180-226) >1000  5.5(4.6-6.5) >1000 AS69 >1000 >100086(77-96) >1000 AS66 467(400-546) >1000  303(260-352) >1000 AS67 2427(2067-2850) >1000 132(98-178) >1000 AS37 140(123-159) >100058(45-74) >1000 AS35 55(46-65)  >1000 34(26-46) >1000 AS60168(140-201) >1000  93(82-105) >1000 AS61 181(127-258) >1000 185(163-210) >1000 AS62 72(45-114) >1000  207(162-265) >1000 AS6349(34-72)  >1000  66(38-116) >1000 AS4 >1000 >1000 >1000 >1000AS20 >1000 >1000 >1000 >1000 AS53  2410(1760-3301) >1000 59(44-81) >1000AS54 448(365-550) >1000 39(33-46) >1000 AS55  1993(1658-2397) >1000 90(73-110) >1000 AS1 >1000 >1000 >1000 >1000 AS49 1440(1250-2211) >1000  81(70-110) >1000 AS91 1005(916-1103) >100074(67-81) >1000 AS92 79(72-86)  >1000 19(12-29) >1000 AS93 >1000 >100086(78-93) >1000 AS95 >1000 >1000 36(27-47) >1000 AS99 700(650-760) >100010(8-13)  >1000 AS100 300(240-380) >1000 16(12-20) >1000AS101 >1000 >1000 12(8-17)  >1000 AS89  955(896-1017) >100041(35-48) >1000 AS70 250(181-348) >1000 15(10-21) >1000 AS72 >1000 >100055(46-65) >1000 AS87 >1000 >1000  122(108-136) >1000 AS90810(763-859) >1000 85(66-95) >1000 AS96 >1000 >1000 24(18-32) >1000AS74 >1000 >1000 47(43-52) >1000 AS76 >1000 >1000 51(44-58) >1000AS73 >1000 >1000 70(61-80) >1000 AS75 >1000 >1000 53(40-69) >1000AS81 >1000 >1000 108(75-155) >1000 AS85 >1000 >1000 >1000 >1000AS94 >1000 >1000 32(22-45) >1000 AS103    81    606    4.9 116

For use as a pharmaceutical preparation, Compound AS68 is particularlypreferred due to its excellent affinity towards the A_(2B) receptor(K_(i)=5.5 nM) despite some significant A₁ adenosine receptor binding(K_(i)=200 nM). Due to strong cardiovascular effects compounds withsignificant A_(2A) binding are less preferred.

For use as a radioligand and where near total A_(2B) receptorselectivity is desired compounds such as AS13, AS15, AS16, AS17, AS28and AS69 are preferred. All have relatively strong A_(2B) receptorbinding (K_(i)=38-103 nM) but without significant binding for any of theother receptor subtypes.

FIGS. 1 through 4 show typical competition curves of compounds AS29,AS57, AS64 and AS68 at A₁, A_(2A), A_(2B), and A₃ A_(2B) and A₃adenosine receptors.

Finally, to evaluate the regulation of adenylyl cyclase activity and totest whether the binding parameters correlated with the functionalresponse, the IC₅0 values were obtained for inhibition of cAMPproduction by antagonists. In particular, we evaluated the capability ofthe several compounds to inhibit NECA (100 nM)-stimulated cyclic AMPaccumulation.

Table 2 summarizes the K_(i) values obtained in [³H]-DPCPX binding toA_(2B) adenosine receptors and the IC₅0 values for the inhibition ofcAMP levels. Of the selected compounds, the most potent adenosine A_(2B)receptor antagonists were AS64 and AS68 (IC₅0=38 and 88 nM,respectively). Compounds AS29 and AS57 show an IC₅0 value of IC₅0=93 and95 nM, respectively (see also FIG. 7). Other tested compounds show anIC₅0 value in the lower nanomolar range (IC₅0=100-1 52 nM,respectively). TABLE 2 Comparison of [³H]-DPCPX Binding to cAMP Levels[³H]-DPCPX binding to human A_(2B) Cyclic AMP assay-human receptors inHEK 293 cells A_(2b) receptors in CHO cells Ki (nM) IC₅₀ (nM) AS 1135(27-45) 103(92-115)  AS 27 28(23-33) 128(114-144) AS 28 38(33-43)120(103-140) AS 29 13(11-16) 93(84-102) AS 35 34(26-46) 152(136-170) AS54 39(33-46) 136(115-161) AS 57 28(12-27) 95(90-101) AS 64 12(7-21) 88(82-95)  AS 65 20(16-25) 108(91-129)  AS 68  5.5(4.6-6.5) 38(29-51) 

Each value of Table 2 is the geometric mean (with 95% confidence limitsin parentheses) of at least three separate experiments performed induplicate.

The Spearman's rank correlation coefficient between affinity values of[³H]-DPCPX binding to A_(2B) adenosine receptor by selected compoundsand the IC₅0 values in the CAMP assay was 0.89 (P<0.01). A comparison ofthe K_(i) and IC₅0 values indicated that high correlation exists betweendata obtained from binding and CAMP assays (FIG. 5).

Formulations

Formulations of the present invention for medical use comprise an activecompound, i.e., a compound of formula (IA) or (IB) together with anacceptable carrier thereof and optionally other therapeutically activeingredients. The carrier must be pharmaceutically acceptable in thesense of being compatible with the other ingredients of the formulationand not deleterious to the recipient thereof.

The present invention, therefore, further provides a pharmaceuticalformulation comprising a compound of formula (IA) or (IB) together witha pharmaceutically acceptable carrier thereof.

The formulations include, but are not limited to, those suitable fororal, rectal, topical or parenteral (including subcutaneous,intramuscular and intravenous) administration. Preferred are thosesuitable for oral, parenteral or topical administration.

The formulations may conveniently be presented in unit dosage form andmay be prepared by any of the methods well known in the art of pharmacy.All methods include the step of bringing the active compound intoassociation with a carrier that constitutes one or more accessoryingredients. In general, the formulations are prepared by uniformly andintimately bringing the active compound into association with a liquidcarrier or a finely divided solid carrier and then, if necessary,shaping the product into desired unit dosage form.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, cachets, tablets orlozenges, each containing a predetermined amount of the active compound;as a powder or granules; or a suspension or solution in an aqueousliquid or non-aqueous liquid, e.g., a syrup, an elixir, an emulsion or adraught.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active compound in a free-flowingform, e.g., a powder or granules, optionally mixed with accessoryingredients, e.g., binders, lubricants, inert diluents, surface activeor dispersing agents. Molded tablets may be made by molding in asuitable machine, a mixture of the powdered active compound with anysuitable carrier.

A syrup or suspension may be made by adding the active compound to aconcentrated, aqueous solution of a sugar, e.g., sucrose, to which mayalso be added any accessory ingredients. Such accessory ingredients) mayinclude flavoring, an agent to retard crystallization of the sugar or anagent to increase the solubility of any other ingredient, e.g., as apolyhydric alcohol, for example, glycerol or sorbitol.

Formulations for rectal administration may be presented as a suppositorywith a conventional carrier, e.g., cocoa butter or Witepsol S55(trademark of Dynamite Nobel Chemical, Germany), for a suppository base.

Formulations suitable for parenteral administration convenientlycomprise sterile aqueous preparation of the active compound that ispreferably isotonic with the blood of the recipient. Thus, suchformulations may conveniently contain distilled water, 5% dextrose indistilled water or saline. Useful formulations also compriseconcentrated solutions or solids containing the compound of formula (I)that upon dilution with an appropriate solvent give a solution suitablefor parental administration above.

Topical formulations include ointments, creams, gels and lotions thatmay be prepared by conventional methods known in the art of pharmacy. Inaddition to the ointment, cream gel, or lotion base and the activeingredient, such topical formulation may also contain preservatives,perfumes, and additional active pharmaceutical agents.

Solutions for use as eyedrops are preferentially prepared by firstaseptically mixing of all the necessary ingredients i.e. the activesubstance, salts and lubricant. If necessary the pH is adjusted to 5-7using solutions of NaOH, KOH, HCl or boric acid. The solution is thensterilized by autoclaving or sterile filtration and filled on one dosepackages.

Solutions can also be prepared by first preparing solutions of each ofthe ingredients and then sterilizing these solutions in the same manneras above before finally mixing and filling the solutions on one dosepackages under aseptic conditions.

In addition to the aforementioned ingredients, the formulations of thisinvention may further include one or more optional accessoryingredient(s) utilized in the art of pharmaceutical formulations, e.g.,diluents, buffers, flavoring agents, binders, surface active agents,thickeners, lubricants, suspending agents, preservatives (includingantioxidants) and the like.

EXAMPLES-PHARMACEUTICAL FORMULATIONS

(A) Transdermal System - for 1000 patches Ingredients Amount Activecompound 100 g Silicone fluid 450 g Colloidal silicon dioxide  2 g

The silicone fluid and active compound are mixed together and thecolloidal silicone dioxide is added to increase viscosity. The materialis then dosed into a subsequent heat sealed polymeric laminate comprisedof the following: polyester release liner, skin contact adhesivecomposed of silicone or acrylic polymers, a control membrane which is apolyolefin, and an impermeable backing membrane made of a polyestermulti-laminate material. The resulting laminated sheet is than cut into10 sq. cm patches (B) Oral Tablet - For 1000 Tablets Ingredients AmountActive compound 50 g Starch 50 g Magnesium Stearate  5 g

The active compound and the starch are granulated with water and dried.Magnesium stearate is added to the dried granules and the mixture isthoroughly blended. The blended mixture is compressed into tablets. (C)Injection - for 1000, 1 mL Ampules Ingredients Amount Active compound 10g Buffering Agents q.s. Propylene glycol 400 mg Water for injection q.s.1000 mL

The active compound and buffering agents are dissolved in the propyleneglycol at about 50° C. The water for injection is then added withstirring and the resulting solution is filtered, filled into ampules,sealed and sterilized by autoclaving. (D) Continuous Injection - for1000 mL Ingredients Amount Active compound 10 g Buffering agents q.s.Water for injection q.s. 1000 mL

(E) Eye Drops - for 100 mL Ingredients Amount Active compound 0.01-1.0 gSodium chloride 0.5-0.09 g Carbachol chloride 0.01-1.0 g Boric acid1.15-3.0 g Water for injection q.s. 100 mL

The eyedrops according to the formulations suggested can be applieddirectly to the eye either upon need or 3-4 times daily.

An aerosol propellant suitable for use in an inhaler can be preparedsimilar to that described in U.S. Pat. No. 6,509,005 to Peart et al.,which is incorporated by reference. (F) Aerosol propellant IngredientsAmount Active compound 0.13% Ethanol   ˜5% Hydrofluoroalkane propellant  95%

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents, modificationsand variations to the specific embodiments of the invention describedherein. For example, other excipients may be utilized in preparing thepharmaceutical formulations. In addition, some of the compoundsdescribed herein contain one or more asymmetric centers and maytherefore give rise to enantiomers and diastereomers as well as theirracemic and resolved, enantiomerically pure or diastereomerically pureforms, and pharmaceutically acceptable salts thereof. Moreover, it willbe appreciated that the general representation of such paired variablesas R³ and R⁴, in compounds of formula (I), is not to be construed as torepresent a particular orientation of the paired members. Accordingly,it is not intended that the present invention be limited to thespecifics of the foregoing description of the preferred embodiments andexample compounds, but rather as being limited only by the scope of theinvention as defined in the claims appended hereto, includingenantiomeric, diastereomeric and pharmaceutical salt forms.

REFERENCES

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1. A method of treating diseases mediated by adenosine A_(2B) receptorscomprising administering to a patient in need of treatment thereof aneffective amount of a compound of formula (I):

wherein R¹and R² are independently hydrogen, (C₁ to C₈)alkyl, (C₂ toC₈)alkenyl, (C₂ to C₈)alkynyl, (C₇ to C₁₄)aralkyl, (C₈ to C₁₄)aralkenyl,or (C₈ to C₁₄)aralkynyl; R³ is hydrogen, (C₁ to C₄)alkyl, (C₂ toC₅)alkenyl, or (C₂ to C₅)alkynyl; A is a carbon-carbon bond, alkyl chainof one to four carbons, alkenyl chain of two to four carbons, or alkynylchain of two to four carbons; X is an optionally substituted five orsix-membered heteroaromatic ring, containing one to four heteroatoms,selected from nitrogen, oxygen, or sulfur, provided that at least oneheteroatom is nitrogen; M is a (C₁ to C₈)alkylene, (C₂ to C₈)alkenylene,or (C₂ to C₈)alkynylene, wherein at least one of the carbon atoms of thealkylene, alkenylene, or alkynylene group is present as a carbonyl, andone or more of the remaining carbon atoms of the alkylene, alkenylene,or alkynylene group may be replaced by —O—, —N(R⁷)—, —S—, —S(O)—, or—S(O)₂—; G¹ and G² are independently CH or N; R⁴, R⁵ and R⁶ areindependently hydrogen, (C₁ to C₄)alkyl, (C₂ to C₅)alkenyl, (C₂ toC₅)alkynyl, optionally substituted (C₆ to C₁₀)aryl, (C₇ to C₁₄)aralkyl,(C₈ to C₁₄)aralkenyl, or (C₈ to C₁₄)aralkynyl, acyl, optionallysubstituted alkoxy, aralkoxyalkylthio, amino, substituted amino,disubstituted amino, fluoro, chloro, bromo, iodo, nitro, cyano, azido,hydroxy, sulflhydryl, S(O)alkyl, S(O)₂alkyl, CO₂H, SO₃H; or takentogether with the carbon atoms to which they are attached either R⁴ andR⁵ or R⁵ and R⁶ form a five or six-membered heterocyclic orheteroaromatic ring containing one to four hetereoatoms selected fromnitrogen, oxygen, or sulfur; or taken together with the carbon atoms towhich they are attached either R⁴ and R⁵ or R⁵ and R⁶ form a carbocyclicor heterocyclic fused ring selected from the group of fused ringscomprising —OCH₂O—, —OCH(R⁷)O—, —OC(R⁷)₂O—, —OCH₂CH₂O—, —OCH₂CH₂—,—CH₂CH₂O—, —OCH₂CH₂CH₂—, —CH₂CH₂CH₂O—, —OCH═CH—, —CH═CH—O—, —O—CH═CH—O—,—CH═CH—CH═CH—, —CH₂CH₂CH₂— and —CH₂CH₂CH₂CH₂—; R⁷ is hydrogen, (C₁ toC₄)alkyl, (C₂ to C₅)alkenyl, or (C₂ to C₅)alkynyl; or a pharmaceuticallyacceptable salt thereof.
 2. The method of claim 1, wherein the treatmentof diseases mediated by adenosine A_(2B) receptors involves treating adisorder selected from the group consisting of chronic and acuteinflammatory diseases involving degranulation of mast cells includingasthma, chronic obstructive pulmonary disease, rheumatoid arthritis,allergic rhinitis, allergic dermatitis and bee sting; impairedsensitivity to insulin including Type 2 diabetes or non-insulindependent diabetes, pre-diabetic state, and impaired glucose tolerance;diseases in which angiogenesis is a key component of pathogenesisincluding solid tumors and angiogenic retinopathies; apnea of preterminfants; myocardial reperfusion injury; inflammatory bowel disease; andautoimmune disease, such as rheumatoid arthritis, multiple sclerosis,and lupus erythematosis.
 3. The method of claim 1, wherein the treatmentof diseases mediated by adenosine A_(2B) receptors involves treating ofasthma.
 4. The method of claim 1, wherein the treatment of diseasesmediated by adenosine A_(2B) receptors involves treating of a disorderselected from the group consisting of microvascular abnormalities of theretina, retinopathy, prematurity, macular degeneration, and diabeticretinopathy.
 5. A method of treating diseases mediated by adenosineA_(2B) receptors comprising administering to a patient in need oftreatment thereof an effective amount of a compound selected from thegroup consisting of:8-(3-amino-1-methyl-1H-pyrazol-5-yl)-1,3-dipropyl-3,7-dihydro-1H-purine-2,6-dione;[3-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)isoxazol-5-yl]methyl-benzoate;8-(1-methyl-4-nitro-1H-pyrrol-2-yl)-1,3-dipropyl-3,7-dihydro-1H-purine-2,6-dione;4-{[5-(1,3-dipropyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]amino}-4-oxobutanoicacid; tert-butyl4-{[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]amino}-4-oxobutylcarbamate;4-{[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]amino}-4-oxobutan-1-aminiumchloride;N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-phenylacetamide;2-(2,4-dichlorophenoxy)-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide;2-(3-methoxyphenyl)-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide;N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(4-isobutylphenyl)acetamide;N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(4-nitrophenyl)acetamide;2-[4-benzyloxyphenyl]-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide;2-[4-hydroxyphenyl]-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide;(2S)-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-phenylpropanamide;(2R)-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-phenylpropanamide;{3-[(E)-2-(1,3-dipropyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)vinyl]isoxazol-5-yl}methylbenzoate; 2-(4-chlorophenoxy)-N-[5-(1,3-dipropyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide;N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(4-fluorophenyl)acetamide;2-(4-methoxyphenyl)-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide;N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(3-chlorophenyl)acetamide;N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(3-fluorophenyl)acetamide;N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-[4-(N,N-dimethylamino)phenyl]acetamide;N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(4-chlorophenyl)acetamide;2-(3,4-dimethoxyphenyl-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide;N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(4-{[2-(trifluoromethyl)benzyl]oxy}phenyl)acetamide;N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(4-{[3-(trifluoromethyl)benzyl]oxy}phenyl)acetamide;N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(4-{4-nitro-benzyloxy}phenyl)acetamide;N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-[4-(trifluoromethyl)phenyl]acetamide;phenyl4-[(E)-2-(7-methyl-1,3-dipropyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)vinyl]-1-methyl-1H-pyrrole-2-carboxylate;N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-5-yl]-2-phenylacetamide;8-(5-amino-1-methyl-1H-pyrazol-5-yl)-1,3-dipropyl-3,7-dihydro-1H-purine-2,6-dione;8-(3-amino-1-methyl-1H-pyrazol-5-yl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione;N-[5-(2,6-dioxo-1,3-dimethyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-phenylacetamide;N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(3,4-difluorophenyl)acetamide;2-(2,3,4-trimethoxyphenyl)-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide;N-[4-(dimethylamino)phenyl]-N′-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]urea;N-(3-chlorophenyl)-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]urea;N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-N′-(3-methoxyphenyl)urea;2-[4-(benzyloxy)-3-methoxyphenyl]-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide;2-(1,3-benzodioxol-5-yl)-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-methyl-1H-pyrazol-3-yl]acetamide;N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(4-hydroxy-3-methoxyphenyl)acetamide;N-(4-methylphenyl)-2-{[5-(1,3-dipropyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]oxy}acetamide;N-(4-bromophenyl)-2-{[3-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-5-yl]oxy}acetamide;N-(4-fluorophenyl)-2-{[3-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-5-yl]oxy}acetamide;2-{[3-(1,3-diisobutyl-2,6-dioxo-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-yl]oxy}-N-(4-fluorophenyl)acetamide;2-{[3-(1,3-diisobutyl-2,6-dioxo-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-5-yl]oxy}-N-(4-bromophenyl)acetamide;2-{[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]oxy}-N-(4-fluorophenyl)acetamide;2-{[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]oxy}-N-(4-bromophenyl)acetamide;2-{[5-(1,3-diisobutyl-2,6-dioxo-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]oxy}-N-(4-fluorophenyl)acetamide;2-{[5-(1,3-diisobutyl-2,6-dioxo-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]oxy}-N-(4-bromophenyl)acetamide;N-1,3-benzodioxol-5-yl-2-{[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]oxy}acetamide;2-{[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]oxy}-N-(4-methoxyphenyl)acetamide;1-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-3-(4-methoxyphenyl)-urea;1,3-di-n-propyl-8-{5-[(4-sec-butyl-phenylcarbamoyl)-methoxy]-2-methyl-2H-pyrazole-3-yl}-xanthine;1,3-di-n-propyl-8-{5-[(4-methyl-phenylcarbamoyl)-methoxy]-2-methyl-2H-pyrazole-3-yl}-xanthine;1,3-di-n-propyl-8-{5-[(4-(morpholine-4-yl)-phenylcarbamoyl)-methoxy]-2-methyl-2H-pyrazole-3-yl}-xanthine;1,3-di-n-propyl-8-{5-[(4-carboxy-phenylcarbamoyl)-methoxy]-2-methyl-2H-pyrazole-3-yl}-xanthine;1,3-di-n-propyl-8-{5-[(3,4-dimethyl-phenylcarbamoyl)-methoxy]-2-methyl-2H-pyrazole-3yl}-xanthine;1,3-di-n-propyl-8-{5-[(3,4-dimethoxy-phenylcarbamoyl)-methoxy]-2-methyl-2H-pyrazole-3-yl}-xanthine;1,3-di-n-propyl-8-{5-[(pyridin-4-yl)-methoxy]-2-methyl-2H-pyrazole-3-yl}-xanthine;1,3-di-n-propyl-8-{5-[2-oxo-2-(4-phenyl-piperazin-1-yl)-ethoxy]-2-methyl-2H-pyrazole-3-yl}-xanthine;8-(5-{2-[4-(4-fluorophenyl)-piperazin-1-yl]-2-oxo-ethoxy}-2-methyl-2H-pyrazol-3-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione;1,3-di-n-propyl-8-{5-[2-oxo-2-(4-methyl-piperazin-1-yl)-ethoxy]-2-methyl-2H-pyrazole-3-yl}-xanthine;8-(5-{2-[4-(4-benzyl-phenyl)-piperazin-1-yl]-2-oxo-ethoxy}-2-methyl-2H-pyrazol-3-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione;1,3-di-allyl-8-{5-[2-oxo-2-(4-phenyl-piperazin-1-yl)-ethoxy]-2-methyl-2H-pyrazole-3-yl}-xanthine;1,3-di-n-propyl-8-{3-[(3,4-methylendioxy-phenylcarbamoyl)-methoxy]-isoxazol-5-yl}-xanthine;1,3-di-n-propyl-8-{3-[(3,4-dimethoxy-phenylcarbamoyl)-methoxy]-isoxazol-5-yl}-xanthine;1,3-di-n-propyl-8-{3-[(4-fluoro-phenylcarbamoyl)-methoxy]-isoxazol-5-yl}-xanthine;1,3-di-n-propyl-8-{3-[(4-methoxy-phenylcarbamoyl)-methoxy]-isoxazol-5-yl}-xanthine;1,3-di-n-propyl-8-{6-[(4-iodo-phenylcarbamoyl)-methoxy]-pyridin-3-yl}-xanthine;1,3-di-n-propyl-8-{6-[(4-iodo-phenylcarbamoyl)-methoxy]-pyridazin-3-yl}-xanthine;N-1,3-benzodioxol-5-yl-2-{[5-(2,6-dioxo-1,3-diallyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]oxy}acetamide;1,3-di-n-propyl-8-{5-[(4-(ethoxycarbonyl)-phenylcarbamoyl)-methoxy]-2-methyl-2H-pyrazole-3-yl}-xanthine;1,3-di-n-propyl-8-(2-hydroxypyridin-5-yl)-xanthine; and1,3-di-n-propyl-8-{5-[(4-(aminosulfonyl)phenylcarbamoyl)-methoxy]-2-methyl-2H-pyrazole-3-yl}-xanthine;or a pharmaceutically acceptable salt thereof.
 6. The method of claim 5,wherein the treatment of diseases mediated by adenosine A_(2B) receptorsinvolves treating a disorder selected from the group consisting ofchronic and acute inflammatory diseases involving degranulation of mastcells including asthma, chronic obstructive pulmonary disease,rheumatoid arthritis, allergic rhinitis, allergic dermatitis and beesting; impaired sensitivity to insulin including Type 2 diabetes ornon-insulin dependent diabetes, pre-diabetic state, and impaired glucosetolerance; diseases in which angiogenesis is a key component ofpathogenesis including solid tumors and angiogenic retinopathies; apneaof preterm infants; myocardial reperfusion injury; inflammatory boweldisease; and autoimmune disease, such as rheumatoid arthritis, multiplesclerosis, and lupus erythematosis.
 7. The method of claim 5, whereinthe treatment of diseases mediated by adenosine A_(2B) receptorsinvolves treating of asthma.
 8. The method of claim 5, wherein thetreatment of diseases mediated by adenosine A_(2B) receptors involvestreating of a disorder selected from the group consisting ofmicrovascular abnormalities of the retina, retinopathy, prematurity,macular degeneration, and diabetic retinopathy.
 9. A method of treatingdiseases mediated by adenosine A_(2B) receptors comprising administeringto a patient in need of treatment thereof an effective amount of acompound selected from the group consisting of:N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-phenylacetamide;2-(3-methoxyphenyl)-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide;N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(4-nitrophenyl)acetamide;2-[4-benzyloxyphenyl]-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide;2-[4-hydroxyphenyl]-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide;N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(4-fluorophenyl)acetamide;2-(4-methoxyphenyl)-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide;N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(3-chlorophenyl)acetamide;N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(3-fluorophenyl)acetamide;N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-[4-(N,N-dimethylamino)phenyl]acetamide;N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(4-chiorophenyl)acetamide;2-(3,4-dimethoxyphenyl)-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide;N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(4-{[2-(trifluoromethyl)benzyl]oxy}phenyi)acetamide;N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(4-{[3-(trifluoromethyl)benzyl]oxy}phenyl)acetamide;N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(4-{4-nitro-benzyloxy}phenyl)acetamide;N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-5-yl]-2-phenylacetamide;8-(5-amino-1-methyl-1H-pyrazol-3-yl)-1,3-dipropyl-3,7-dihydro-1H-purine-2,6-dione;N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(3,4-difluorophenyl)acetamide;N-[4-(dimethylamino)phenyl]-N′-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]urea;N-(3-chlorophenyl)-N′-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]urea;N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-N′-(3-methoxyphenyl)urea;2-[4-(benzyloxy)-3-methoxyphenyl]-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide;2-(1,3-benzodioxol-5-yl)-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-methyl-1H-pyrazol-3-yl]acetamide;N-(4-bromophenyl)-2-{[3-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-5-yl]oxy}acetamide;2-{[3-(1,3-diisobutyl-2,6-dioxo-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-5-yl]oxy}-N-(4-bromophenyl)acetamide;2-{[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]oxy}-N-(4-fluorophenyl)acetamide;2-{[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]oxy}-N-(4-bromophenyl)acetamide;2-{[5-(1,3-diisobutyl-2,6-dioxo-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]oxy}-N-(4-bromophenyl)acetamide;N-1,3-benzodioxol-5-yl-2-{[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]oxy}acetamide;and2-{[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]oxy}-N-(4-methoxyphenyl)acetamide;or a pharmaceutically acceptable salt thereof.
 10. The method of claim9, wherein the treatment of diseases mediated by adenosine A_(2B)receptors involves treating a disorder selected from the groupconsisting of chronic and acute inflammatory diseases involvingdegranulation of mast cells including asthma, chronic obstructivepulmonary disease, rheumatoid arthritis, allergic rhinitis, allergicdermatitis and bee sting; impaired sensitivity to insulin including Type2 diabetes or non-insulin dependent diabetes, pre-diabetic state, andimpaired glucose tolerance; diseases in which angiogenesis is a keycomponent of pathogenesis including solid tumors and angiogenicretinopathies; apnea of preterm infants; myocardial reperfusion injury;inflammatory bowel disease; and autoimmune disease, such as rheumatoidarthritis, multiple sclerosis, and lupus erythematosis.
 11. The methodof claim 9, wherein the treatment of diseases mediated by adenosineA_(2B) receptors involves treating of asthma.
 12. The method of claim 9,wherein the treatment of diseases mediated by adenosine A_(2B) receptorsinvolves treating of a disorder selected from the group consisting ofmicrovascular abnormalities of the retina, retinopathy, prematurity,macular degeneration, and diabetic retinopathy.
 13. A method of treatingdiseases mediated by adenosine A_(2B) receptors comprising administeringto a patient in need of treatment thereof an effective amount of acompound selected from the group consisting of:2-(3-methoxyphenyl)-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide;N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(4-nitrophenyl)acetamide;2-[4-benzyloxyphenyl]-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide;2-[4-hydroxyphenyl]-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide;N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-[4-(N,N-dimethylamino)phenyl]acetamide;2-(3,4-dimethoxyphenyl)-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide;8-(3-amino-1-methyl-1H-pyrazol-5-yl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione;N-[5-(2,6-dioxo-1,3-dimethyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-phenylacetamide;N-(4-methylphenyl)-2-{[5-(1,3-dipropyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]oxy}acetamide;and2-{[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]oxy}-N-(4-methoxyphenyl)acetamide;or a pharmaceutically acceptable salt thereof.
 14. The method of claim13, wherein the treatment of diseases mediated by adenosine A_(2B)receptors involves treating a disorder selected from the groupconsisting of chronic and acute inflammatory diseases involvingdegranulation of mast cells including asthma, chronic obstructivepulmonary disease, rheumatoid arthritis, allergic rhinitis, allergicdermatitis and bee sting; impaired sensitivity to insulin including Type2 diabetes or non-insulin dependent diabetes, pre-diabetic state, andimpaired glucose tolerance; diseases in which angiogenesis is a keycomponent of pathogenesis including solid tumors and angiogenicretinopathies; apnea of preterm infants; myocardial reperfusion injury;inflammatory bowel disease; and autoimmune disease, such as rheumatoidarthritis, multiple sclerosis, and lupus erythematosis.
 15. The methodof claim 13, wherein the treatment of diseases mediated by adenosineA_(2B) receptors involves treating of asthma.
 16. The method of claim13, wherein the treatment of diseases mediated by adenosine A_(2B)receptors involves treating of a disorder selected from the groupconsisting of microvascular abnormalities of the retina, retinopathy,prematurity, macular degeneration, and diabetic retinopathy.
 17. Amethod of treating diseases mediated by adenosine A_(2B) receptorscomprising administering to a patient in need of treatment thereof aneffective amount of a compound of formula (IA):

wherein R¹ and R² are independently (C₁ to C₃)alkyl or allyl; A is acarbon-carbon bond; X is selected from the group consisting of

M is selected from the group consisting of —NHC(O)CH₂—, —NHC(O)CH₂O—,—NHC(O)CH(CH₃)—, and —NHC(O)NH—; R⁴, R⁵ and R⁶ are independentlyhydrogen, (C₁ to C₄)alkyl, (C₂ to C₅)alkenyl, (C₂ to C₅)alkynyl,optionally substituted (C₆ to C₁₀)aryl, (C₇ to C₁₄)aralkyl, (C₈ toC₁₄)aralkenyl, or (C₈ to C₁₄)aralkynyl, acyl, optionally substitutedalkoxy, aralkoxy, amino, substituted amino, disubstituted amino, fluoro,chloro, bromo, nitro, hydroxy, CO₂H; or taken together with the carbonatoms to which they are attached either R⁴ and R⁵ or R⁵ and R⁶ form afive or six-membered heterocyclic or heteroaromatic ring containing oneto four hetereoatoms selected from nitrogen, oxygen, or sulfur; or takentogether with the carbon atoms to which they are attached either R⁴ andR⁵ or R⁵ and R⁶ form a heterocyclic fused ring in which either R⁴ and R⁵or R⁵ and R⁶ combined are —OCH₂O—; or a pharmaceutically acceptable saltthereof.
 18. The method of claim 17, wherein the treatment of diseasesmediated by adenosine A_(2B) receptors involves treating a disorderselected from the group consisting of chronic and acute inflammatorydiseases involving degranulation of mast cells including asthma, chronicobstructive pulmonary disease, rheumatoid arthritis, allergic rhinitis,allergic dermatitis and bee sting; impaired sensitivity to insulinincluding Type 2 diabetes or non-insulin dependent diabetes,pre-diabetic state, and impaired glucose tolerance; diseases in whichangiogenesis is a key component of pathogenesis including solid tumorsand angiogenic retinopathies; apnea of preterm infants; myocardialreperfusion injury; inflammatory bowel disease; and autoimmune disease,such as rheumatoid arthritis, multiple sclerosis, and lupuserythematosis.
 19. The method of claim 17, wherein the treatment ofdiseases mediated by adenosine A_(2B) receptors involves treating ofasthma.
 20. The method of claim 17, wherein the treatment of diseasesmediated by adenosine A_(2B) receptors involves treating of a disorderselected from the group consisting of microvascular abnormalities of theretina, retinopathy, prematurity, macular degeneration, and diabeticretinopathy.
 21. A method of treating diseases mediated by adenosineA_(2B) receptors comprising administering to a patient in need oftreatment thereof an effective amount of a compound of formula (IB):

wherein R¹ and R² are independently (C₁ to C₄)alkyl; A is acarbon-carbon bond; X is selected from the group consisting of

M is —OCH₂C(O)NH—; G¹ and G² are independently CH or N; R⁴, R⁵ and R⁶are independently hydrogen, (C₁ to C₄)alkyl, (C₂ to C₅)alkenyl, (C₂ toC₅)alkynyl, optionally substituted (C₆ to C₁₀)aryl, (C₇ to C₁₄)aralkyl,(C₈ to C₁₄)aralkenyl, or (C₈ to C₁₄)aralkynyl, acyl, optionallysubstituted alkoxy, aralkoxy, amino, substituted amino, disubstitutedamino, fluoro, chloro, bromo, nitro, hydroxy, CO₂H; or taken togetherwith the carbon atoms to which they are attached either R⁴ and R⁵ or R⁵and R⁶ form a five or six-membered heterocyclic or heteroaromatic ringcontaining one to four hetereoatoms selected from nitrogen, oxygen, orsulfur; or taken together with the carbon atoms to which they areattached either R⁴ and R⁵ or R⁵ and R⁶ form a heterocyclic fused ringcomprising —OCH₂O—; or a pharmaceutically acceptable salt thereof. 22.The method of claim 21, wherein the treatment of diseases mediated byadenosine A_(2B) receptors involves treating a disorder selected fromthe group consisting of chronic and acute inflammatory diseasesinvolving degranulation of mast cells including asthma, chronicobstructive pulmonary disease, rheumatoid arthritis, allergic rhinitis,allergic dermatitis and bee sting; impaired sensitivity to insulinincluding Type 2 diabetes or non-insulin dependent diabetes,pre-diabetic state, and impaired glucose tolerance; diseases in whichangiogenesis is a key component of pathogenesis including solid tumorsand angiogenic retinopathies; apnea of preterm infants; myocardialreperfusion injury; inflammatory bowel disease; and autoimmune disease,such as rheumatoid arthritis, multiple sclerosis, and lupuserythematosis.
 23. The method of claim 21, wherein the treatment ofdiseases mediated by adenosine A_(2B) receptors involves treating ofasthma.
 24. The method of claim 21, wherein the treatment of diseasesmediated by adenosine A_(2B) receptors involves treating of a disorderselected from the group consisting of microvascular abnormalities of theretina, retinopathy, prematurity, macular degeneration, and diabeticretinopathy.
 25. A method of treating diseases mediated by adenosineA_(2B) receptors comprising administering to a patient in need oftreatment thereof an effective amount of a compound of formula (IC):

wherein R¹ and R² are independently (C₁ to C₃)alkyl; R³ is hydrogen ormethyl; A is selected from the group consisting of a carbon-carbon bondand —CH═CH—; X is

M is —CH₂OC(O)—; R⁴, R⁵ and R⁶ are independently hydrogen, (C₁ toC₄)alkyl, (C₂ to C₅)alkenyl, (C₂ to C₅)alkynyl, optionally substituted(C₆ to C₁₀)aryl, (C₇ to C₁₄)aralkyl, (C8 to C₁₄)aralkenyl, or (C₈ toC₁₄)aralkynyl, acyl, optionally substituted alkoxy, aralkoxy, amino,substituted amino, disubstituted amino, fluoro, chloro, bromo, nitro,hydroxy, CO₂H; or taken together with the carbon atoms to which they areattached either R⁴ and R⁵ or R⁵ and R⁶ form a five or six-memberedheterocyclic or heteroaromatic ring containing one to four hetereoatomsselected from nitrogen, oxygen, or sulfur; or a pharmaceuticallyacceptable salt thereof.
 26. The method of claim 25, wherein thetreatment of diseases mediated by adenosine A_(2B) receptors involvestreating a disorder selected from the group consisting of chronic andacute inflammatory diseases involving degranulation of mast cellsincluding asthma, chronic obstructive pulmonary disease, rheumatoidarthritis, allergic rhinitis, allergic dermatitis and bee sting;impaired sensitivity to insulin including Type 2 diabetes or non-insulindependent diabetes, pre-diabetic state, and impaired glucose tolerance;diseases in which angiogenesis is a key component of pathogenesisincluding solid tumors and angiogenic retinopathies; apnea of preterminfants; myocardial reperfusion injury; inflammatory bowel disease; andautoimmune disease, such as rheumatoid arthritis, multiple sclerosis,and lupus erythematosis.
 27. The method of claim 25, wherein thetreatment of diseases mediated by adenosine A_(2B) receptors involvestreating of asthma.
 28. The method of claim 25, wherein the treatment ofdiseases mediated by adenosine A_(2B) receptors involves treating of adisorder selected from the group consisting of microvascularabnormalities of the retina, retinopathy, prematurity, maculardegeneration, and diabetic retinopathy.
 29. A method of treatingdiseases mediated by adenosine A_(2B) receptors comprising administeringto a patient in need of treatment thereof an effective amount of acompound of formula (I):

wherein R¹ and R² are independently hydrogen, (C₁ to C₈)alkyl, (C₂ toC₈)alkenyl, (C₂ to C₈)alkynyl, (C₇ to C₁₄)aralkyl, (C₈ to C₁₄)aralkenyl,or (C₈ to C₁₄)aralkynyl; R³ is hydrogen, (C₁ to C₄) alkyl, (C₂ toC₅)alkenyl, or (C₂ to C₅)alkynyl; A is a carbon-carbon bond, alkyl chainof one to four carbons, alkenyl chain of two to four carbons, or alkynylchain of two to four carbons; X is a five or six-membered heteroaromaticring, containing one to four heteroatoms, selected from nitrogen,oxygen, or sulfur, provided that at least one heteroatom is nitrogen,optionally substituted by one or two substituents selected from thegroup consisting of lower alkyl, amino, hydroxy, alkyloxy, acyloxy andacylamino; M is a (C₁ to C₈)alkylene, (C₂ to C₈)alkenylene, or (C₂ toC₈)alkynylene, wherein at least one of the carbon atoms of the alkylene,alkenylene, or alkynylene group is present as a carbonyl, and one ormore of the remaining carbon atoms of the alkylene, alkenylene, oralkynylene group may be replaced by —O—, —N(R⁷)—, —S—, —S(O)—, or—S(O)₂—; or a carbon substituted with a lower alkyl group; G¹ and G² areindependently CH or N; R⁴, R⁵ and R⁶ are independently hydrogen, (C₁ toC₄)alkyl, (C₂ to C₅)alkenyl, (C₂ to C₅)alkynyl, optionally substituted(C₆ to C₁)aryl, (C₇ to C₁₄)aralkyl, (C₈ to C₁₄)aralkenyl, or (C₈ toC₁₄)aralkynyl, acyl, optionally substituted alkoxy, aralkoxyalkylthio,amino, substituted amino, disubstituted amino, fluoro, chloro, bromo,iodo, nitro, cyano, azido, hydroxy, sulflhydryl, S(O)alkyl, S(O)₂alkyl,CO₂H, SO₃H; or taken together with the carbon atoms to which they areattached either R⁴ and R⁵ or R⁵ and R⁶ form a five or six-memberedheterocyclic or heteroaromatic ring containing one to four hetereoatomsselected from nitrogen, oxygen, or sulfur; or taken together with thecarbon atoms to which they are attached either R⁴ and R⁵ or R⁵ and R⁶form a carbocyclic or heterocyclic fused ring selected from the group offused rings comprising —OCH₂O—, —OCH(R⁷)O—, —OC(R⁷)₂O—, —OCH₂CH₂O—,—OCH₂CH₂—, —CH₂CH₂O—, —OCH₂CH₂CH₂—, —CH₂CH₂CH₂O—, —OCH═CH—, —CH═CH—O—,—O—CH═CH—O—, —CH═CH—CH═CH—, —CH₂CH₂CH₂— and —CH₂CH₂CH₂CH₂—; R⁷ ishydrogen, (C₁ to C₄)alkyl, (C₂ to C₅)alkenyl, or (C₂ to C₅)alkynyl; or apharmaceutically acceptable salt thereof.
 30. The method of claim 29,wherein the treatment of diseases mediated by adenosine A_(2B) receptorsinvolves treating a disorder selected from the group consisting ofchronic and acute inflammatory diseases involving degranulation of mastcells including asthma, chronic obstructive pulmonary disease,rheumatoid arthritis, allergic rhinitis, allergic dermatitis and beesting; impaired sensitivity to insulin including Type 2 diabetes ornon-insulin dependent diabetes, pre-diabetic state, and impaired glucosetolerance; diseases in which angiogenesis is a key component ofpathogenesis including solid tumors and angiogenic retinopathies; apneaof preterm infants; myocardial reperfusion injury; inflammatory boweldisease; and autoimmune disease, such as rheumatoid arthritis, multiplesclerosis, and lupus erythematosis.
 31. The method of claim 29, whereinthe treatment of diseases mediated by adenosine A_(2B) receptorsinvolves treating of asthma.
 32. The method of claim 29, wherein thetreatment of diseases mediated by adenosine A_(2B) receptors involvestreating of a disorder selected from the group consisting ofmicrovascular abnormalities of the retina, retinopathy, prematurity,macular degeneration, and diabetic retinopathy.
 33. A method of treatingdiseases mediated by adenosine A₂3 receptors comprising administering toa patient in need of treatment thereof an effective amount of a compoundof formula (I):

wherein: R¹ and R² are each n-propyl; R³ is hydrogen; A is acarbon-carbon bond; X is

M is —NHC(O)CH₂—; G¹ and G² are each CH; R⁴ and R⁶ are hydrogen; R⁵ isbenzyloxy: or a pharmaceutically acceptable salt thereof.
 34. The methodof claim 33, wherein the treatment of diseases mediated by adenosineA_(2B) receptors involves treating a disorder selected from the groupconsisting of chronic and acute inflammatory diseases involvingdegranulation of mast cells including asthma, chronic obstructivepulmonary disease, rheumatoid arthritis, allergic rhinitis, allergicdermatitis and bee sting; impaired sensitivity to insulin including Type2 diabetes or non-insulin dependent diabetes, pre-diabetic state, andimpaired glucose tolerance; diseases in which angiogenesis is a keycomponent of pathogenesis including solid tumors and angiogenicretinopathies; apnea of preterm infants; myocardial reperfusion injury;inflammatory bowel disease; and autoimmune disease, such as rheumatoidarthritis, multiple sclerosis, and lupus erythematosis.
 35. The methodof claim 33, wherein the treatment of diseases mediated by adenosineA_(2B) receptors involves treating of asthma.
 36. The method of claim33, wherein the treatment of diseases mediated by adenosine A_(2B)receptors involves treating of a disorder selected from the groupconsisting of microvascular abnormalities of the retina, retinopathy,prematurity, macular degeneration, and diabetic retinopathy.
 37. Amethod of treating diseases mediated by adenosine A_(2B) receptorscomprising administering to a patient in need of treatment thereof aneffective amount of a compound of formula (III):

wherein: R¹ and R² are independently hydrogen, (C₁ to C₈)alkyl, (C₂ toC₈)alkenyl, (C₂ to C₈)alkynyl, (C₇ to C₁₄)aralkyl, (C₈ to C₁₄)aralkenyl,or (C₈ to C₁₄)aralkynyl; R⁸ is phenyl, halogen substituted phenyl, (C₁to C₈)alkyl, or benzyl; or a pharmaceutically acceptable salt thereof.38. The method of claim 37, wherein the treatment of diseases mediatedby adenosine A_(2B) receptors involves treating a disorder selected fromthe group consisting of chronic and acute inflammatory diseasesinvolving degranulation of mast cells including asthma, chronicobstructive pulmonary disease, rheumatoid arthritis, allergic rhinitis,allergic dermatitis and bee sting; impaired sensitivity to insulinincluding Type 2 diabetes or non-insulin dependent diabetes,pre-diabetic state, and impaired glucose tolerance; diseases in whichangiogenesis is a key component of pathogenesis including solid tumorsand angiogenic retinopathies; apnea of preterm infants; myocardialreperfusion injury; inflammatory bowel disease; and autoimmune disease,such as rheumatoid arthritis, multiple sclerosis, and lupuserythematosis.
 39. The method of claim 37, wherein the treatment ofdiseases mediated by adenosine A_(2B) receptors involves treating ofasthma.
 40. The method of claim 37, wherein the treatment of diseasesmediated by adenosine A_(2B) receptors involves treating of a disorderselected from the group consisting of microvascular abnormalities of theretina, retinopathy, prematurity, macular degeneration, and diabeticretinopathy.